All Cyborgs Now: Hippocampal Pacemaker in Alzheimer's

This article is adapted from an article published on Al Fin Longevity




Johns Hopkins researchers are implanting electronic "pacemaker" devices in the brain fornix -- the nerve input to the hippocampus -- in Alzheimer's patients. This study is a follow-on to an earlier Canadian study which showed promising results for such a procedure.

The surgery involves drilling holes into the skull to implant wires into the fornix on either side of the brain. The fornix is a brain pathway instrumental in bringing information to the hippocampus, the portion of the brain where learning begins and memories are made, and where the earliest symptoms of Alzheimer’s appear to arise. The wires are attached to a pacemaker-like device, the "stimulator," which generates tiny electrical impulses into the brain 130 times a second. The patients don’t feel the current, Rosenberg says.

For the trial, all of the patients will be implanted with the devices. Half will have their stimulators turned on two weeks after surgery, while the other half will have their stimulators turned on after one year. Neither the patients nor the doctors treating them will know which group gets an early or later start.

"Deep brain stimulation might prove to be a useful mechanism for treating Alzheimer’s disease, or it might help us develop less invasive treatments based on the same mechanism," Rosenberg says.

By 2050, the number of people age 65 and older with Alzheimer’s disease may triple, experts say, from 5.2 million to a projected 11 million to 16 million, unless effective treatments are found. _Johns Hopkins _via_ ExtremeLongevity

The actual deficit in Alzheimer's involves multiple breakdowns in both neural pathways and processing centres of the brain. A "brain pacemaker" which keeps the hippocampus primed and healthy, should help tremendously in the early and middle stages of the disease. It may even prolong the early and middle stages -- postponing the final decline of mental function.

But to actually cure Alzheimer's disease, scientists will need to understand the underlying processes and predispositions much more clearly.

In the meantime, any route to improvement and mitigation is likely to be welcome, by most sufferers and their families.

Daily Mail report on this story

Going On the Offensive Against Dementia

This article is re-posted from the Al Fin Longevity blog


Rather than fighting a rear-guard action against advancing dementia, some researchers are taking an offensive approach -- a "procognitive" approach. This means that instead of trying to slow down the inevitable decline of dementia, these researchers aim to rebuild brain tissues and brain function. They aim to push back against the decline and reverse it.

Scientists have developed a small peptide that they say can reverse some of the cognitive repercussions of neurodegenerative and potentially trauma-related brain disorders such as Alzheimer’s disease, by increasing synaptogenesis. The peptide, called dihexa, is a stabilized derivative of angiotensin IV (AngIV)...

...Washington State University’s Joseph W. Harding, Ph.D., Alene T. McCoy, Ph.D., and colleagues based their development on prior work demonstrating that the three terminal amino acids of AngIV and its analog Norleucine1-angiotensin IV (Nle1-AngIV) are central to the precognitive activities of the peptides. The team thus set out to develop much smaller, more stable derivatives of Nle1-AngIV that retained the active structure but could be administered orally and cross the blood-brain barrier.

The resulting lead compound, dihexia (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) not only fulfilled these requirements, but proved to be active at picomolar concentrations, and led to dramatic improvements in the cognitive abilities of a scopolamine-treated rat model of learning deficits, and also aged Sprague-Dawley rats.

Importantly, the treatment was effective whether the animals received it directly into the brain, via injection, or orally. Further analyses indicated that dihexia’s precognitive activity was associated with a drug-induced stimulation of dendritic spinogenesis in the hippocampal brain region, and that the newly formed dendritic spins were creating functional synapses. Encouragingly, dihexia was even more potent than brain-derived neurotrophic factor (BDNF), a growth-promoting protein that is used to create neuronal connections, but which hasn’t yet been developed for therapeutic use.

“At its core dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex,” the researchers note in their published paper in the Journal of Pharmacology and Experimental Therapeutics. However, previous attempts to develop protein neurotrophic factors as therapeutics has been limited by their inability to cross the blood-brain barrier, and the need to manufacture such agents by recombinant methods, which is costly. “The development of dihexa has seemingly overcome these impediments by virtue of its oral activity, demonstrated pro-cognitive/anti-dementia activity, and anticipated low manufacturing costs.” _Gen Engineering News

Another interesting candidate for procognitive therapy is ABT-288, an H3 receptor antagonist.

Another very interesting class of procognitive drugs is the Ampakines. Ampakine CX546 is a recent drug candidate undergoing study.

Here are two different approaches to procognition in the context of developing novel anti-psychotic drugs:

Egis 11150 which has broad spectrum adrenergic, serotenergic, and dopaminergic antagonist activity
New anti-psychotics with 5HT2C receptor agonist and 5HT6 receptor antagonist activity

It is important for neuropharmacologists to take this fateful step, of taking the offensive in the fight against dementia. Repairing and rebuilding the damaged tissues in the brain will likely get better results than a piecemeal promotion of this neurotransmitter, or combating this protein or another. A procognitive approach holds out the possibility of a return to normal function, rather than a mere slowing of inevitable decline.

The technology of the early diagnosis of future dementia is advancing on multiple fronts, from better brain scanners to genetic testing to two recent interesting developments:

Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Not only does VRFCAT promise to provide early diagnosis of cognitive problems, but it should also prove useful for monitoring of different therapeutic regimens.

New mathematical approaches to model the brain as a complex network of interconnected processing nodes Such mathematical modeling approaches should provide new ways of diagnosing normal vs. impaired brain network activity, as well as new ways to monitor effects of therapies on brain network function.

Eventually, what we will want from procognitive treatments, is for all of us to be able to become capable of clearer and deeper thought. For now, we will be happy to watch dementia sufferers coming back into themselves.

But once we see that beginning to happen, we are likely to want to "spread the wealth around" to include more and more people, maybe even ourselves.

Single Drug Treatment for Alzheimer's, MS, TBI, and More

In a study published in the Journal of Neuroscience, a collaborative team of researchers led by Linda J. Van Eldik, director of the University of Kentucky Sanders-Brown Center on Aging, and D. Martin Watterson of the Northwestern University Feinberg School of Medicine, present results showing that a new central nervous system drug compound can reduce Alzheimer’s pathology in a mouse model of the disease.

The drug, called MW-151, is a selective suppressor of brain inflammation and overproduction of pro-inflammatory molecules from glial cells. The drug can be taken by mouth and readily enters the brain. The new study tested the hypothesis that intervention with drugs like MW-151 could be effective as a preventive measure, when administered at an early stage before Alzheimer's pathology appears, as well as after disease symptoms have begun to appear. _Source

The UK / Northwestern team has developed two drugs in this new class -- MW 151 and MW 189. This new class of drugs protects the brain by limiting production of and preventing the accumulation of pro-inflammatory cytokines in the brain. Inflammation in the brain can be particularly destructive in a wide range of infections, diseases, traumatic injuries, vascular insufficiencies, and more.

When too many of the cytokines are produced, the synapses of the brain begin to misfire. Eventually the entire organization of the brain falls into disarray, like a computer failing. The neurons lose their connections with each other and can eventually die. The resulting damage in the cortex and hippocampus can compromise memory and decision-making.

"In Alzheimer's disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer's as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other," said Watterson, the John G. Searle Professor of Molecular Biology and Biochemistry. "And high levels of proinflammatory cytokines can contribute to synaptic malfunction."

Because this harmful inflammatory mechanism also appears to be a major player in other neurodegenerative disorders in addition to Alzheimer's, the class of drugs represented by MW151 might hold bright potential as co-therapies for Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, M.S. and the longer term complications of brain injury, Watterson said. _MedXpress

It is likely that this new class of drugs with its very broad spectrum of affects will find application in a wide range of conditions -- some not yet anticipated.

Regardless of neuro-inflammation’s exact role, a prevailing hypothesis is that targeting of pro-inflammatory cytokine overproduction in the brain might be a useful therapeutic strategy to add to the armamentarium of emerging interventions. The primary brain cell target for such a disease modifying strategy would be glia, cells in the brain that produce pro-inflammatory cytokines and other innate immunity responses to injury or disease progression. Glial cells normally cooperate with the nerve cells to keep the brain operating smoothly. When an injury or change in the brain occurs, the glial cells mount a beneficial inflammation response to fight off the insult and restore the brain to its proper functioning. This beneficial process sometimes gets out of balance and the inflammation becomes too strong or does not shut off on schedule. _SurfKy

Mastering Dynamic Cell Signaling

The following article was first published on Al Fin Longevity blog

Cells make decisions in fluctuating environments using inherently noisy biochemical mechanisms. Such effects create considerable, unpredictable variation – known as ‘stochasticity’– both over time and between genetically identical cells. To understand how cells exploit and control these biochemical fluctuations, scientists must identify the sources of stochasticity, quantify their effects, and distinguish variation that carries information about the biological environment from confounding noise.

In their PNAS paper, Dr Bowsher and Professor Swain show how to decompose the fluctuations of biochemical networks into multiple components and how to design experimental ‘reporters’ to measure these components in living cells.

The paper, which describes the application of this approach to yeast cells, shows that the majority of cellular variation may be informational in origin and due to fluctuations in the cellular environment. The results pave the way to a better understanding of the dynamics of signal processing and decision-making by cells. _SD

Cell Signaling Network, Preliminary Sketch
We begin to comprehend the potential power of cell signaling mastery, when we observe research breakthroughs such as the following:

In laboratory experiments with mouse cells, the researchers found that a specific protein that regulates cell aging also controls a process that causes blood-making stem cells to age. Using drugs to inhibit the action of this protein (called Cdc42) reversed aging of the hematopoietic stem cells and restored their function to a level similar to that of younger stem cells.

It had been [previously] believed that the aging of hematopoietic stem cells was locked in by nature and could not be reversed by using drugs, according to a hospital news release.

...The study by scientists at Cincinnati Children's Hospital Medical Center and Ulm University Medicine in Germany appeared online May 3 in the journal Cell Stem Cell. _USN

Turning old hematopoietic stem cells into young hematopoietic stem cells is nothing to sneeze at. And it is only a slight foretaste of what is becoming possible, as we better understand cell signaling networks and the signaling involved in gene expression.

One of the more exciting near-to-intermediate term possibility arising from the coming mastery of cell signaling, is the ability to reverse neurodegenerative diseases which involve abnormal protein folding. Diseases such as Alzheimer's, Huntington's, Parkinson's, and "mad cow disease," for example, involve abnormal proteins leading to cell destruction and loss of neural function.

Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.

They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.

...The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.

Each neuro-degenerative disease results in a unique set of misfolded proteins being produced, which are then thought to lead to brain cells dying.

Prof Giovanna Mallucci told the BBC: "The novelty here is we're just targeting the protein shut-down, we're ignoring the prion protein and that's what makes it potentially relevant across the board."

The idea, which has not yet been tested, is that if preventing the shut down protects the brain in prion disease - it might work in all diseases that have misfolded proteins.

Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders. _BBC

Nature article

Complex cell signaling is also involved in the control of gene expression, including critically important DNA repair, and control of telomere length in cells -- which controls the number of cell doublings allowed.

If you click on the image above, you can view an enlarged version of a portion of a cell signaling network. Such complexity explains the need for high powered computational backup in the attempt to decode these networks, as a prelude to their mastery.

Cellular processes take place very quickly, and in a closely controlled and balanced chemical milieu. If we are to learn to intervene on the level of the cell in a beneficial way, we must proceed with care. But we definitely aim to proceed.

A New Angle of Attack Against Alzheimer's Dementia

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.

...EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer's dementia aim to either affect the levels of neurotransmitters in the brain -- particularly acetylcholine -- or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer's is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer's. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer's disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer's Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted to Al Fin Longevity

Bonus: Rather far-out reading for extra credit -- http://www.dhushara.com/cosfcos/cosfcos2.html. The fascinating webpage at the link ties into the theme of brain microtubules, via the much debated idea of a microtubular quantum coding involvement in human consciousness. Most readers will want to skip this topic, but for the obsessive compulsives among the Al Fin readership, it may prove interesting. More from the online Journal of Cosmology

MIT Neuroscientists Make Important Alzheimer's Discovery

The number of Alzheimer’s victims worldwide is expected to double every 20 years... MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans.

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer’s symptoms in mice._MIT

As the populations of the developed and emerging nations grow progressively older, the number of Alzheimer's sufferers -- and sufferers of other debilitating diseases of old age -- threaten to cripple these societies. Affordable means of preventing and treating dementias and other disabling diseases of senescence could make the difference between prosperity or poverty for many nations. The recent MIT discovery may be an important step forward in this regard.

... the team subsequently showed that using RNAi to reduce HDAC2 build up in the hippocampus of a mouse neurodegenerative disease model removed this repression, reinstated neuronal structural and synaptic plasticity, and eradicated neurodegeneration-associated memory deficits. Li-Huei Tsai, Ph.D., and colleagues report their findings in Nature in a paper titled “an epigenetic blockade of cognitive functions in the neurodegenerating brain.”

Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.

To further investigate the role of HDAC2 in neurodegeneration-related cognition, the team looked at levels of the enzyme in CK-p25 mice. These animals can be induced to overexpress p25, in the forebrain. p25 is a truncated version of p35 and is implicated in a range of neurodegenerative diseases. Their studies showed that animals induced to overexpress p25 demosntrated significant increases in HDAC2 in neuronal nuclei, specifically hippocampal area CA1 but not CA3 or the dentate gyrus, and also in the prefrontal cortex. In contrast, levels of the HDAC1 and HDAC3, were not changed.

The researchers then moved on to carry out chromatin immunopreciptation studies to assess the functional consequences of HDAC2 elevation, primarily in a range of known HDAC2 targets that have been shown to be downregulated in human AD brains, including learning- and memory-related genes, and those involved in synaptic plasticity. They found elevated HDAC2 enrichment at the majority of these genes induced CK-p25 hippocampus, whereas again, HDAC1 and HDAC3 binding wasn’t affected. “Interestingly, in agreement with previous reports showing that HDAC2 can also bind to a gene’s coding region, we also found HDAC2 more abundantly bound to the coding sequence of the same genes,” they note. _GenengNews

The MIT researchers have utilised a number of different advances in cell and molecular biology to make these discoveries. As scientists close in on the discovery of meaningful interventions in destructive pathological processes, the importance of pre-existing replicated "off the shelf" research grows.

The researchers found that in mice with Alzheimer’s symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

“It’s not just one or two genes, it’s a group of genes that work in concert to control different phases of memory formation,” Tsai says. “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function. _MIT

This is good news for all mice who suffer from Alzheimer's. Now, scientists must confront the immense government-made mine field and obstacle course which obstruct modern efforts to affordably develop life saving interventions in the biomedical fields. In this sense -- as in many others -- government is the greatest enemy of the future.

Cross-posted to Al Fin Longevity

Reversing Alzheimer's Disease w/ Deep Brain Electro-Stim

BRAIN shrinkage in people with Alzheimer's disease can be reversed in some cases - by jolting the degenerating tissue with electrical impulses. Moreover, doing so reduces the cognitive decline associated with the disease. _NS

NS
Alzheimer's disease is an increasingly common cause of total disability in the ageing population. One of the manifestations of Alzheimer's is a shrinking and shutting down of activity in multiple centres of the brain which are critical to memory function. Cells die and crucial brain tissue is lost, as part of the disease process. Now scientists at Toronto Western Hospital in Ontario, believe they may have found an effective approach -- for some.

The group inserted electrodes into the brains of six people who had been diagnosed with Alzheimer's at least a year earlier. They placed the electrodes next to the fornix - a bundle of neurons that carries signals to and from the hippocampus - and left them there, delivering tiny pulses of electricity 130 times per second.

Follow-up tests a year later showed that the reduced use of glucose by the temporal lobe and posterior cingulate had been reversed in all six people (Annals of Neurology, DOI: 10.1002/ana.22089).

The researchers have now begun to investigate the effects on the hippocampus. At the Society for Neuroscience annual meeting in Washington DC last week they announced that while they saw hippocampal shrinking in four of the volunteers, the region grew in the remaining two participants.

"Not only did the hippocampus not shrink, it got bigger - by 5 per cent in one person and 8 per cent in the other," says Lozano. It's an "amazing" result, he adds.

Tests showed that these two individuals appeared to have better than expected cognitive function, although the other four volunteers did not.

Though Lozano is not sure exactly how the treatment works, his team's recent work in mice suggests that the electrical stimulation might drive the birth of new neurons in the brain. Deep brain stimulation in mice also triggers the production of proteins that encourage neurons to form new connections _NS

This approach is worth pursuing further. It is too invasive to be used on a wide scale, but it is likely that there will be no shortage of volunteers for the procedure. What is learned from this research can be used to devise less invasive approaches which will be more appropriate for use in larger populations.

In the meantime, research into the use of pharmaceuticals, growth factors, and stem cell therapies for Alzheimer's will continue.

Cross-posted from Al Fin Longevity

New Hope for Restoring Lost Memory

Researchers estimate that roughly 20 to 30 percent of people age 75 and older have elevated glucocorticoid levels (more precise figures aren't available). Most affected is so-called declarative memory, the ability to learn new facts and remember, for example, lists. People who suffer age-related memory loss are at higher risk for developing Alzheimer's and other forms of dementia, though the condition is not itself considered a form of dementia. _TechnologyReview

A research team at the University of Edinburgh have developed a new compound that appears to prevent and reverse age-related memory decline in mice. Their approach utilises a "gene knockout" approach against an amplifier of glucocorticoid effect present in brain cells.

"What's most surprising is that even short-term inhibition was able to reverse memory loss in old mice," says Jonathan Seckl, a professor of molecular medicine who was involved in the research. "I don't think people had realized this was so reversible. It takes [the animals] back to being relatively young."

The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.

Scientists have long known that glucocorticoids--a class of steroid hormones that mediate our response to stressful situations--play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.

Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, "this enzyme acts as an intracellular amplifier of glucocorticoids," says Seckl. "If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear."

The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals' memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice--the maximum lifespan for a typical lab mouse--was enough to improve the animals' performance on a test of spatial memory. The treatment "returned mice to the equivalent of when they were young and fully functioning," says Brian Walker, another researcher involved in the study. "It's important to emphasize that we are trying to target the pathology--the role that glucocorticoids play in age-related memory decline--not just globally improving memory." The research was published last week in the Journal of Neuroscience. _TechnologyReview

Brian Wang looks at another approach to augmenting human brainpower

Top 50 Online Resources for Families Coping with Alzheimer's -- A Guest Article by Rachel Davis

Top 50 Online Resources for Families Coping With Alzheimer’s

Alzheimer’s disease is so cruel—it robs our loved ones of their senses of self, of their mental capacities, of their memories, of their lives. And it forces spouses and children to become caregivers in ways that most people never imagine. With millions of people each year being diagnosed with Alzheimer’s or a similar dementia, and millions more dying from it, it is still possible for caregivers to feel lost, confused, and alone. We’ve searched the Web to find some of the most helpful resources for families coping with Alzheimer’s. Hopefully, this top 50 list provides you with some information, inspiration, and even comfort.

Personal Blogs By Caregivers

These blogs have been written by children and spouses of Alzheimer’s sufferers.

1. The Yellow Wallpaper : A heart-rending account of a daughter and mother’s story of love and loss to Alzheimer’s disease. 2. Alzheimer’s Moments : A son chronicles the life of his mother in a nursing home for residents with Alzheimer’s and dementia. 3. The Zen of Caregiving : An artist struggling with her own bipolar disorder journals about her daily life caring for a husband with Alzheimer’s. 4. Early Onset Alzheimer’s Adventure : Chuck D’Onofrio has been blogging about his diagnosis with Alzheimer’s disease since 2006. 5. blog.fadingfrommemory.info : Compelling blog about a family’s struggle with Alzheimer’s disease when both parents were diagnosed. 6. Dorian Martin’s SharePosts : Dorian Martin cared for her mother with Alzheimer’s from 2005 to 2007, upon her passing. Her blog shares the ups and downs of being a caregiver. 7. “had a dad” Alzheimer’s Blog : Gereva Bert Piedmont writes this blog as a way to share memories of her late father and to support others going through the struggle with Alzheimer’s. 8. All Your Blogs Are Belong to Us : Heart-wrenching stories from a man who has lost his mother and two brothers to early-onset Alzheimer’s disease. 9. Alzheimer’s Support : Sandy shares stories of her mother and provides links and resources to families dealing with this diagnosis. 10. caringformary.blogspot.com : This blogger relates her story of the Alzheimer’s diagnosis of her mother and the last stages of her life. 11. Never Goodbye : A woman relates the story of her father’s diagnosis, treatment, and death from Alzheimer’s. 12. The Mom & Me Journals dot Net : An amazing body of work from a daughter who became her mother’s end-of-life companion in the year 1993 until her death in 2008.

Information About Alzheimer’s Disease

13. Alzheimer’s Disease – Symptoms Treatment and Care : Articles about Alzheimer’s disease and other resources are included here. 14. holisticnutritionandneurology.blogspot.com : Doctors discuss the connections between nutrition and neurological disorders, including Alzheimer’s. 15. EverydayHealth.com : Everyday Health provides suggestions and contact information for various Alzheimer’s support organizations. 16. The Tangled Neuron : Mona Johnson provides the latest updates on Alzheimer’s research, written in a way that families can understand. 17. Alzheimer’s Association : The Alzheimer’s Association provides excellent resources on their website. 18. alzheimers247.wordpress.com : There are several good articles about Alzheimer’s Disease on this blog. 19. PBS.org: The Forgetting : This is a wonderful companion website to the gripping PBS documentary,The Forgetting, which originally aired in 2008. 20. Partnering With Your Doctor: A Guide For Persons With Memory Problems and Their Care Partners : This excellent online brochure is provided by the Alzheimer’s Association and helps patients and their caregivers know how to work with the doctor. 21. Alzheimer’s Reading Room : This is the #1 blog online in the category of Alzheimer’s and Caregiving. Over 1,500 articles deal with topics from anxiety to behavior problems. 22. AHAF : You can order free brochures from the American Health Assistance Foundation on this site devoted to Alzheimer’s research. 23. Brain Today : Two doctors and a medical professional blog daily about news in the world of neurosciences and Alzheimer’s Disease. 24. About.com : Coping With Alzheimer’s : About.com has many excellent articles about ways to cope with a diagnosis of Alzheimer’s Disease. 25. Dementia News : A British website that combines many different resources about the effects of dementia, including Alzheimer’s. 26. Mayo Clinic: Alzheimer’s Disease – Coping and support : The Mayo Clinic offers advice to both the Alzheimer’s patient and the caregiver. Subscribe to the free newsletter. 27. Coping With Daily Life and Alzheimer’s Disease : Alzheimer’s patients who are still aware of their condition and that they are losing their mental capacity have many questions as they wonder how to cope with the disease.

Survival Skills For The Caregiver

28. Tips for Traveling With An Alzheimer’s Patient : Alzcare.net provides excellent tips for traveling with an Alzheimer’s patient. 29. Alzcast.org : Alzcast.org is a website designed for doctors, nurses, and caregivers. The site features podcasts from different experts on all aspects of dealing with Alzheimer’s. 30. Medicare For Caregivers : Anyone who is caring for an elderly relative will appreciate the resources available on this site. Learn all about Medicare coverage and the benefits that are available to your loved one. 31. The CareGiver : Bob DeMarco uses this blog to discuss the many issues that concern Alzheimer’s caregivers on a daily basis. 32. Wego Health : Dementia Support at Wego Health includes many helpful links to online support resources. 33. Activity Ideas That Work : Gina Salazar writes about activities that are appropriate for Alzheimer’s patients. 34. Helpguide.org : Helpguide.org provides well-researched information on Alzheimer’s and dementia, providing resources for caregivers. 35. The Nursing Home Administrator : Insight into the world of the nursing home administrator, someone who may become an important person in your life if your family is dealing with Alzheimer’s disease. 36. Caregiver Support Page at Caring.com : Interact with other caregivers at Caring.com and read many good articles about ways to cope with Alzheimer’s disease in a loved one. 37. Alzheimer’s Caregiver’s Corner : The Alzheimer’s Caregiver’s Corner is provided by the Fisher Center for Alzheimer’s Research Foundation. It has links to many articles about being a good caregiver. 38. Exelon Patch: For The Caregiver : The makers of Exelon provide helpful resources for people dealing with mild to moderate Alzheimer’s disease. 39. The Unforgettable Fund : The Unforgettable Fund was begun by the McNally family after losing their father to Alzheimer’s Disease. 40. Medicare Florida : This blog combines many different resources for families coping with Alzheimer’s. 41. 1,2,3: Steps 4 Family Caregivers : This free online brochure reminds caregivers to take care of themselves, reach out for help, and believe in themselves. 42. 10 Tips for Communicating with a Person with Dementia : This is a helpful article from the Family Caregivers Alliance. 43. Take Care of Yourself: 10 Ways to be a Healthier Caregiver : This is an excellent checklist that gives caregivers easy strategies for improving their own health. 44. Life Without Memories : This page was created to help support Alzheimer’s patient caregivers and spread news about research developments. 45. Caregiver Relief : Donahue Vanderhider is a gerontologist who specializes in helping caregivers manage stress. 46. bigtreemurphy.com : Beverly Bigtree Murphy, author of he used to be Somebody, provides amazing resources for people who wish to take care of an Alzheimer’s patient at home. She cared for her husband for 14 years after his diagnosis. 47. Caring for a Person with Alzheimer’s Disease: Your Easy-to-Use Guide from the National Institute on Aging. : 48. Dementia, Caregiving and Controlling Frustration. : This page has a great article about dealing with the frustration that so many caregivers face. 49. CareGiverUnderGround : Linda has taken her experiences as a caregiver as well as good outside resources and put them all together in this original blog. It’s designed to give caregivers support and inspiration. 50. KnowItAlz : KnowItAlz, an online community just for Alzheimer’s caregivers, provides a wealth of resources and support.

This guest article comes courtesy of Rachel Davis at Radiology Degree.com

Redeeming Older Brains: Possible New Alzheimer's Wonderdrugs

New nerve cells are constantly born in the hippocampus, but even in the normal adult brain, most of these newborn neurons die before they become functional.

And they fare much worse in the hippocampus of Alzheimer's patients.

Physical activity, an active social life and other intellectually and emotionally enriching experiences promote the birth and maturation of new neurons.

The scientists wanted to find compounds that can protect newborn neurons from dying.

P7C3 was selected from among about 1,000 compounds tested on mice.

The compound was found to help the survival of neurons in adult mice, which were genetically engineered to lack a gene that is crucial for the survival of newborn nerve cells. _IndiaToday

ScienceDaily
University of Texas Southwestern have reported in Cell the discovery of a molecule -- P7C3 -- that has the ability to protect brain cells, and trigger the production of new neurons. The scientists believe that new compounds in the same class as P7C3 may hold the key to slowing or temporarily reversing the progress of Alzheimer's Disease and other neurodegenerative conditions.

In a new study published today in the journal Cell, researchers screened 1000 molecules in mice to see which ones enhanced production of new neurons in a brain area involved in learning and memory. This region, known as the hippocampus, is one of two spots known to birth new neurons in the adult mammalian brain. It takes 2 to 4 weeks for the cells to migrate to the appropriate location and integrate into the existing neural circuitry, and many of them die along the way.

The researchers found that one compound, dubbed P7C3, protected these newborn neurons from dying. When given to mice genetically engineered to have very little new nerve cell growth, the compound seemed to repair the abnormal hippocampus. It could also increase birth and survival of new neurons in older rats, according to a press release from UT Southwestern Medical Center. The animals also had improved memory: they could better remember the location of a platform submerged in water, a standard test of learning and memory in rodents.

...

According to a release from the journal Cell, where the paper was published;

Two other drugs (Dimebon and Serono compounds) - both of which bear structural similarities to P7C3 -also encourage the growth of new neurons. It's tempting to think that all three compounds work in the same way.

In fact, Dimebon first came to the attention of researchers based on anecdotal reports by Russian physicians that the drug may ameliorate the symptoms of age-related cognitive decline. Unfortunately, unpublished reports from a phase 3 clinical trial have since failed to provide evidence that the drug could stave off the memory loss that comes with Alzheimer's disease.

In light of the new findings, it may be worth another look. "The speculative idea that these chemicals share a common mode of action will only be rigorously tested upon identification of their molecular target(s)."

 _TechnologyReview

Pieper, McKnight and colleagues tested more than 1000 small molecules in living mice. One of the compounds, designated P7C3, corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells -- normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers discovered that it protects the integrity of machinery for maintaining a cell's energy level.
To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.
Prolonged treatment of aged rats with P7C3 also enhanced the birth of new neurons. "Aged rats normally show a decline in neurogenesis associated with an inability to form new memories and learn tasks," Pieper explained.

In their study, rats treated with P7C3 each day showed evidence of an increase in the formation of newborn neurons and significant improvements in their ability to swim to the location of a missing platform, a standardized test of learning and memory in rats.

The researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer's cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer's disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 -- key to discovering the underlying neuroprotective mechanism. _ScienceDaily

The study was two-tiered: First the scientists screened over a thousand small molecules in knockout mice, to find the one that provided the best protection for new hippocampal neurons. Then they tested the compound in senescent rats, looking for both behavioural improvements and better survival of new hippocampal neurons. They were successful on all counts.

H/T Brian Wang of NextBigFuture

Will America Have the Money to Treat Dementia?

• As many as 5.2 million people in the United States are living with Alzheimer’s.

• 10 million baby boomers will develop Alzheimer's in their lifetime.

• Every 71 seconds, someone develops Alzheimer’s.

• Alzheimer's is the sixth-leading cause of death [US].

• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $148 billion each year. _Alz

The older you get, the more likely that you will suffer some form of cognitive impairment -- most likely Alzheimer's. With the aging of North America and the developed world, the need for better ways to diagnose and treat Alzheimer's is critical.

New cognitive tests are being developed to determine whether a person with early cognitive impairment can drive safely. Special MRI techniques can show the early tell-tale signs of Alzheimer brain atrophy.

On the treatment side, "brain games" that develop short term memory appear helpful in reversing early cognitive impairment.

Another hopeful bit of news is that Rember and Dimebon -- two novel drug treatments for Alzheimer's -- are working their way through human drug trials, and show some promise.

A bit further in the future is the promise of Ampakines. Cortex Pharmaceuticals is the foremost developers of Ampakines for a wide range of disorders -- including Alzheimer's in the long run.

Further into the future, an even wider array of drugs are being developed to target several pathological mechanisms that are believed to contribute to Alzheimer's.

The main question at this time appears to involve financing for drug discovery and testing in the midst of an international financial crisis. US governmental policies under the new administration suggest that US pharmaceutical research and research into other vital innovative technologies will be short-changed. New drug development may well move offshore from the US to East and South Asia, where capital is less likely to be diverted to non-productive ends.

It is ironic that just when a relaxation of stem cell research regulations occurs, that a misconceived and dysfunctional economic re-structuring should threaten the future of technological development in the biosciences and most other high tech fields.

Previously published at Al Fin Longevity

....And That is the Reason That My Skin is Blue

It isn't easy to live longer than a century. A human being requires some help to avoid cancer, heart disease, Alzheimer's, and other maladies that cut a life short of its useful span. Methylene Blue, a simple heterocyclic aromatic, can be of some benefit in that regard.

A new study conducted by researchers at Children's Hospital & Research Center Oakland shows that a century-old drug, methylene blue, may be able to slow or even cure Alzheimer's and Parkinson's disease. Used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water – the drug slows cellular aging and enhances mitochondrial function, potentially allowing those with the diseases to live longer, healthier lives.

A paper on the methylene blue study, conducted by Hani Atamna, PhD, and a his team at Children's, was published in the March 2008 issue of the Federation of American Societies for Experimental Biology (FASEB) Journal. Dr. Atamna's research found that methylene blue can prevent or slow the decline of mitochondrial function, specifically an important enzyme called complex IV. Because mitochondria are the principal suppliers of energy to all animal and human cells, their healthy function is critical. _SD

First the urine turns blue, then the lymph, and finally the skin. It is a bitter pill to swallow, but growing old must be more bitter still.

Alzheimer's Progress: Two New Drugs

In the UK, a new drug called Rember appears to target "Tau tangles" in the portion of the brain most active in memory formation.

The drug, Rember, targets the build-up of tau protein tangles which form inside the brain nerve cells of people with Alzheimer's. These tangles destroy nerve cells linked to memory, causing forgetfulness.

Professor Claude Wischik of Aberdeen University in northeast Scotland, who co-founded the company which created the drug, hailed the results as "the most significant development in the treatment of the tangles since Alois Alzheimer discovered them in 1907".
_AFP

Meanwhile at the Alzheimer's conference in Chicago (ICAD 2008) new results for a drug designated Al-108 were announced.

One Phase II trial, of a compound called AL-108, targeted early abnormal brain changes in a protein called "tau" in a condition related to Alzheimer's called mild cognitive impairment (MCI: 24.15, -0.43, -1.74%). The researchers saw improvement on various measures of memory....

"Twelve weeks of AL-108 treatment given intranasally by spray resulted in a statistically significant, dose-dependent and durable improvement on measures of short-term memory, including visual, verbal, and auditory working memory, which is a type of memory function that deteriorates throughout the progression of Alzheimer's," Schmechel said.

"This makes AL-108 the first drug to validate in humans the importance of the 'tangle' or 'tau' pathway in Alzheimer's. Based on these results in MCI, there are plans for further development of AL-108 in Alzheimer's," Schmechel added.
_Source

Other studies presented at the Chicago conference suggested that diabetes drugs including insulin may reduce the size of Alzheimer's brain plaques.

In addition to the above new drugs, the antihistamine Dimebon and the anti-arthritis drug Etanercept are being studied intensively after early promising research findings. Chana de Wolf presents more information on the TNF-alpha modulation effect of etanercept at Depressed Metabolism blog.

This progress comes at a time when some studies indicate that mild cognitive impairment (MCI) is far more common than previously thought, often beginning in the 50's, and progressing to dementia over a period of years or decades.

Brian Wang has more on Al-108

Obscure Russian Antihistamine May Point to Key Weakness of Alzheimer's Disease

183 Russian Alzheimer's patients were studied for a year to compare the safety and efficacy of Dimebon, an obscure antihistamine that is not on the market anywhere in the world. The study was conducted by Baylor College of Medicine researchers, and published in the Lancet.

In the study, the authors noted that Dimebon is the first drug for Alzheimer's disease that demonstrated continued improvement in patients over a 12 month period. Other approved drugs do not have this effect.

Half of the 183 patients in the Russian study received Dimebon; the other half were given a placebo or an inactive pill. Clinicians at the study sites then monitored the patients' progress over the next year on five different outcomes. All of those in the study had mild to moderate Alzheimer's disease.

"What we saw in the clinical trial is that people on the medication continued to improve over time," Doody said. "Those on placebo continued to decline."

Researchers believe the medication works by stabilizing mitochondria, the cellular components that produce energy, and possibly by inhibiting brain cell death. Researchers evaluated patients' thinking and memory ability, overall function, psychiatric and behavioral symptoms, and ability to perform daily activities.

"Usually at this point in a drug's development, we are happy to see improvement in one of the outcome measures," Doody said. "We saw improvement in all five." _SD

The study was reportedly well-designed and conducted. The significant and ongoing improvement of the drug group over the placebo group for at least a year, is quite impressive. Rights for the drug are owned by Medivation, Inc. (Nasdaq: MDVN), which has enjoyed a recent boost in stock price.

Update: A Washington Post article from today's edition has more about this study, as well as updates on other research approaches to treating AD. Excerpt:

The study was done in Russia because dimebon had been approved there as an antihistamine. Dimebon is made by the San Francisco-based biopharmaceutical company Medivation. Doody is on the Scientific and Clinical Advisory Board of Medivation and has stock options in the company.

Another phase III trial has just started, Doody said. This six-month trial is being conducted in the United States, Europe and South America and is now in the process of recruiting several hundred patients, she noted.

Brain Rejuvenation Using Intravenous Cord Blood

Image Source

Researchers in Florida have managed to rejuvenate the brains of aging mice with a single injection of human cord blood cells in a peripheral vein. The single cord blood cell injection resulted in new progenitor stem cells in the mouse hippocampus, and new nerve cell formation.

Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.

The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

...Not only do the results of this study provide novel insight into the state of the aged stem cell niche, the ability of the UCBMC to exert their effects while being administered minimally invasively may make translation to the clinical setting more likely. For this reason it will be important in future studies to determine the most efficacious dose and dosing regimen. Nevertheless, this is the first time that a systemic injection of hematopoietic cells has been shown to restore the regenerative potential of the aged brain, providing a novel insight into how the regenerative potential of the aged stem cell niches could be restored.

...The effects of UCBMC have been attributed to changes in the microenvironment of the brain, through the release of trophic factors or by reducing inflammation, and not by a direct replacement of cells [21-23]. UCBMC contains a number of cell types including B-Cells and T-Cells, as well as, mesenchymal and endothelial progenitor cells. UCBMC is also a rich source of CD34⁺ hematopoietic stem cells [24-26]. It was recently demonstrated that a systemic injection of UCBMC cells could suppress inflammation in the brain following stroke. Moreover, the effects of UCBMC cells seemed to shift the cytokine expression from a Th1 response to a Th2 response [20,23,27]. In addition to the immune modulatory effects, UCBMC cells also produce a number of trophic factors including, but not limited to, VEGF, nerve growth factor, and cytokine colony stimulating factor-1, thrombopoietin, and IL11 [20,28,29]. ___BiomedCentral__via_madscience__via__TechnutNews

It is important to understand that the cells that were injected into the peripheral veins of mice were human umbilical cord blood mononuclear cells (HUCBMCs). The results are somewhat startling, given that the injected cells were not neural stem cells, the cells were not injected directly into the brain, and the cells were given in a single dose only. It will be important for the researchers to tease out the important cellular and trophic factors present in the UCBMC's that may have led to the rejuvenatory effects.

This is a line of research that I am interested in following further.

New Alzheimer's Treatment Approach

An excess of Beta amyloid protein in Alzheimer's patients leads to amyloid plaques and eventual neuronal death. One new approach to treating Alzheimer's is to block the enzymes that cleave the longer protein "APP" into Amyloid Beta, or A Beta.

The molecule, called a beta-secretase inhibitor, prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.

The study of 48 healthy volunteers showed dose-related reduction in plasma amyloid beta, a protein believed to be a key biomarker of Alzheimer's. Results showed a single dose of the drug produced a greater than 60 percent reduction of the biomarker. Subjects received one of six different doses or a placebo, and the study measured levels of the therapeutic drug and levels of the biomarker in the bloodstream.

"The phase I clinical results are very exciting," Ghosh said. "We hope that this beta-secretase inhibitor drug will be one of the first disease modifying treatments that stops or reverses the symptoms of Alzheimer's disease."

Science Daily

Several new approaches to Alzheimer's treatment are aimed at the A Beta protein--either in preventing its overproduction, or in speeding its elimination. Here is an interesting approach--a vaccine against Amyloid Beta. These approaches have the potential to prevent the onset or full manifestation of Alzheimer's, once diagnosed or strongly suspected. Better screening tests and genetic tests should allow good selection of candidates for various primary and secondary preventive strategies.


Image credit

The Poor Man's TNF Blocker: Curcumin

Enbrel (Etanercept), an anti-arthritis drug, has recently been shown to improve cognition in Alzheimer's Disease patients, via Tumour Necrosis Factor (TNF) blocking. Even if Etanercept was approved for treating AD, a yearly dose of Enbrel would cost an Alzheimer's patient US $30,000 per year.

Curcumin (turmeric), a root spice used in Indian cooking, also blocks TNF. In addition, curcumin crosses the blood-brain-barrier readily. Prevalence of AD in Indian seniors is less than half the prevalence of AD in North Americans. Combining those facts suggests that Indians may be protected from Alzheimer's Disease by the contents of their diet, possibly via at least one of the same pathways that the drug Enbrel protects against AD.

In some studies in AD model mice, Beta Amyloid levels in mice given curcumin were reduced by 40% compared to levels in mice not given curcumin. Above a certain dose level of curcumin, the amyloid reduction affect of curcumin was diminished, however.

North American researchers have studied curcumin for protective effects in cancer and sepsis, and more recently have begun looking at curcumin for AD prevention. The common pathway for those diseases that is blocked by curcumin is our old friend, the NFkappaB pathway, triggered by TNF, among other things.

With the knowledge that AD is worsened by multiple TNF effects on glial cells in the brain, the importance of locating effective TNF inhibitors grows more urgent.

This article presents several other pharmacological effects of curcumin.

More information about the awakening of western medicine to Curcumin.

Nice article on curcumin by John Smart

Enbrel: Etanercept -- A New Conceptual Approach for Treating Alzheimer's and Other Diseases

Enbrel (Etanercept) is a Tumour Necrosis Factor (TNF) blocker originally developed to treat arthritis (RA and JRA). Its use has been enlarged to treat psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. Even more astounding, Etanercept has shown efficacy in treating forms of diabetes, advanced heart failure, and most recently, Alzheimer's Disease.

Of particular relevance to intersections between neuroinflammation and neurodegeneration is the ability of TNF to increase expression of interleukin-1 (IL-1), which in turn increases production of the precursors necessary for formation of amyloid plaques, neurofibrillary tangles, and Lewy bodies. More recent data have revealed that TNF, one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction. Toward such manipulation in Alzheimer's disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, an FDA-approved TNF inhibitor that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients.

How rapid were these improvements? Would you believe, for some patients, "in minutes?"

The drug, called Enbrel, is injected into the spine where it blocks a chemical responsible for damaging the brain and other organs.

A pilot study carried out by U.S. researchers found one patient had his symptoms reversed "in minutes".

Other patients have shown some improvements in symptoms such as forgetfulness and confusion after weekly injections over six months.

The study of 15 patients with moderate to severe Alzheimer's has just been published in the Journal of Neuroinflammation by online publishers Biomed Central.

... Sue Griffin, a researcher at the University of Arkansas for Medical Sciences, said: 'It is unprecedented to see cognitive and behavioural improvement in a patient with established dementia within minutes of therapeutic intervention.

'This gives all of us in Alzheimer research a tremendous new clue about new avenues of research.' Enbrel is not approved for treating Alzheimer's in the U.S. or the UK and is regarded as highly experimental, said Dr Griffin.

Source

There is also evidence that Etanercept can normalize mitochondrial function in some conditions. Clearly, TNF-mediated inflammation plays a significant role in a very broad array of disease processes.

While the vast majority of such research findings take place in the western world, the benefits from their discovery will quickly disseminate to the far corners of the entire world. This is one dimension of the "seed effect" of a freer intellectual environment within the west. What a shame to ever lose that.

To watch a fascinating animation of TNF and Etanercept at work, go here.

HSP90, Cancer, and Sepsis

HSP90 is a heat shock protein--proteins in the cell that become more concentrated in reaction to cellular stresses, including heat. HSP90 also has normal, non-stress functions in the cell--particularly chaperone functions. As a chaperone, HSP90 helps to keep proteins from folding in aberrant and dysfunctional conformations.

HSP90 inhibitors have recently come into play for the treatment of malignancies. HSP90 tends to reduce (through re-folding and other pro-degradation processes) the concentration of apoptotic products coming from early cancer cells--allowing the cells to grow longer and become more difficult to treat with conventional cancer treatments. Inhibiting HSP90 leads to more apoptosis of cancer cells, and more effective cancer treatment.Researchers have recently begun to look at HSP90 inhibitors for treating sepsis and other conditions of extreme inflammation in the body.

Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

...These manmade HSP 90 inhibitors work by attaching where the protein pair's energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.

Source

Getting down to the level of folding and re-folding of proteins is an important step for pharmacologists and protein scientists. This is where the rubber meets the road in cellular function. It should not go unsaid that there are important lessons here for nanotechnologists as well.

By understanding how to lock, unlock, and modify active sites of proteins--and controlling their energetics and shape--protein scientists are in essence bio-nanotechnologists.

One Pill to Stop Smoking AND Drinking? How'd They Do That?

Smoking tobacco and drinking alcohol go together like sweating and mowing the lawn. So is it really so surprising that a pill that is approved in the US for smoking cessation, may also work as an aid for alcoholics to stop drinking?

The drug, called varenicline, already is sold to help smokers kick the habit. New but preliminary research suggests it could gain a second use in helping heavy drinkers quit, too.

Much further down the line, the tablets might be considered as a treatment for addictions to everything from gambling to painkillers, researchers said.

....Pfizer Inc. developed the drug specifically as a stop-smoking aid and has sold it in the United States since August under the brand name Chantix. Varenicline works by latching onto the same receptors in the brain that nicotine binds to when inhaled in cigarette smoke, an action that leads to the release of dopamine in the brain's pleasure centers. Taking the drug blocks any inhaled nicotine from reinforcing that effect.

A study published Monday suggests not just nicotine but alcohol also acts on the same locations in the brain. That means a drug like varenicline, which makes smoking less rewarding, could do the same for drinking. Preliminary work, done in rats, suggests that is the case.

"The biggest thrill is that this drug, which has already proved safe for people trying to stop smoking, is now a potential drug to fight alcohol dependence," said Selena Bartlett, a University of California, San Francisco neuroscientist who led the study. Details appear this week in the journal Proceedings of the National Academy of Sciences.

Pfizer provided the drug for the study, but was not otherwise involved in the research.

....Several experts not involved in the study cautioned that there is no such thing as a magic cure-all for addiction and that varenicline and similar drugs may find more immediate use in treating diseases like Alzheimer's and Parkinson's.

Source

This is rather fascinating, when you think about it. Of course we all know there is no cure-all for addiction. Otherwise, the inventor of such a cure-all would now be the world's richest person, and we would all have read about it.

Nevertheless, there are few drugs on the market that affect the brain's nicotinic receptor system directly--other than nicotine itself--and this drug is interesting if for no other reason than that. This drug may actually prove to be more effective for treating Alzheimer's Disease than for treating alcoholism--time will tell.

The exact mechanisms of the reward systems in the brain, and how nicotinic receptors are involved, is still being worked out. But the brain's reward system is very central to human motivations and behaviours. This drug and analogs of this drug should prove very useful in ongoing research to tease out the intricacies of these systems.