Beta Amyloid and Alzheimer's: What it Does, How to Stop it

Beta Amyloid protein, Abeta, is involved in neuron damage in several diseases, including Alzheimer's. A recent report from Johns Hopkins has solidly established the association between Beta Amyloid and memory loss in a mouse model of Alzheimer's.

A research team that included members from The Johns Hopkins University and the University of Minnesota Medical School has for the first time identified a substance in the brain that is proven to cause memory loss. This identification gives drug developers a target for creating drugs to treat memory loss in patients with dementia.

....The researchers hypothesized that there was a substance in the brain that causes memory decline that is present even before nerve cells begin to die. To test that hypothesis, the team used mice whose genetic makeup was manipulated to develop memory loss much in a way people develop subtle memory problems before the earliest stages of Alzheimer's disease. Using mice that showed early signs of memory loss and had no plaques or nerve cell loss in the brain, they discovered a form of the amyloid-beta protein that is distinct from plaques. They extracted and purified this newly found protein complex and injected it into healthy rats. The rats suffered cognitive impairment, confirming that this protein has a detrimental effect on memory.

Read the full report here.

We learn even more about beta amyloid, and how it kills brain cells in alzheimer's, from this research report from Children's Hospital and Recearch Center, Oakland.

In a study published in the February 28th issue of the Proceedings of the National Academy of Sciences, lead scientist Hani Atamna, Ph.D., found that alterations in the production of heme (a molecule that contains iron) may be the key to understanding why excessive amyloid-beta is toxic to brain cells. Dr. Atamna had previously discovered that Alzheimer's patients have abnormal amounts of heme in their brains. In new research results, Atamna's team showed that amyloid-beta readily binds with heme to form a compound that can be flushed from cells. When there is insufficient heme or too much amyloid-beta, however, the amyloid-beta forms large toxic "clumps" that the cell cannot dissolve and eliminate.

Though heme binding with amyloid-beta can be beneficial, if too much heme is bound up with amyloid-beta, there may be insufficient heme available for the cell to properly function. When this happens, the cell's mitochondria, which are the tiny structures inside brain cells that produce the energy the cells need to function, begin to decay. Dr. Atamna refers to this phenomenon as a "functional heme deficiency" because the cells are still forming heme, but it is trapped within an amyloid-beta/heme compound.

When they examined the heme/ amyloid-beta compound researchers in the Atamna laboratory were surprised to discover it was a peroxidase--a type of enzyme that reacts harmfully with biological materials essential for proper brain function such as serotonin and L-DOPA. Dr. Atamna believes that the combination of functional heme deficiency, which harms mitochondria needed to produce energy, together with the increase in oxidative damage caused by the peroxidase, is what eventually kills the cell.

So we can see that beta amyloid first causes confusion and memory loss, then it binds heme and triggers oxidative damage to neurons, and mitochondrial dysfunction leading to apoptosis of the neuron. Now we need to look at ways to prevent and arrest those processes before the damage is irrevocable.

In this research report, we learn how researchers used Herpes Simplex Virus (HSV) as a vector for gene therapy, to inhibit amyloid beta production and accumulation.

We generated replication-defective herpes simplex virus (HSV) vectors that inhibit Abeta accumulation, both in vitro and in vivo. In cell culture, HSV vectors expressing either (i) short hairpin RNA directed to the APP transcript (HSV-APP/shRNA), or (ii) neprilysin, an endopeptidase that degrades Abeta (HSV-neprilysin), substantially inhibited accumulation of Abeta. To determine whether these vectors showed similar activity in vivo, we developed a novel mouse model, in which overexpression of a mutant form of APP in the hippocampus, using a lentiviral vector (LV-APP(Sw)), resulted in rapid Abeta accumulation. Co-inoculation of LV-APP(Sw) with each of the HSV vectors showed that either HSV-APP/shRNA or HSV-neprilysin inhibited Abeta accumulation in this model, whereas an HSV control vector did not. These studies demonstrate the utility of HSV vectors for reducing Abeta accumulation in the brain, thus providing useful tools to clarify the role of Abeta in AD that may facilitate the development of novel therapies for this important disease.Gene Therapy advance online publication, 16 March 2006

Read more here.

There is a great deal more involved with Alzheimer's than what is discussed in these three articles. You may be wondering where the beta amyloid protein came from in the first place. This useful review article will help to answer that question, and discusses several present and future treatments for Alzheimer's as well. It may take an hour or two to read and digest, but while doing so, be thankful you have that capacity.

There are many, many unanswered questions remaining. But since Alzheimer's is considered a priority by most western governments, well designed research that addresses those questions is very likely to be funded.