11 February 2006

Alzheimer's Disease Puzzle: New Key to Prevention

For over a decade, scientists have known that apolipoprotein E4 (apoE4) is associated with susceptibility to Alzheimer's disease. Slowly, neuroscientists are accumulating more details about the actual mechanism by which apoE4 leads to neurological damage in Alzheimer's. In this ScienceDaily news release, Georgetown Neuroscientists, Rebeck and Hoe, present more details about this connection:

the research team specifically found that receptors on the outside of brain nerve cells (neurons) that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein.

While the scientists don't know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories.

"We have found out that two receptors previously thought to have nothing to do with each other do, in fact, interact, leading us to conclude that APOE affects the NMDA glutamate channel that is important in memory," says the study's senior author, G. William Rebeck, PhD, associate professor of neuroscience in Georgetown's Biomedical Graduate Research Organization.

...In work leading up to this study, Rebeck and the research team found that adding APOE to neurons in laboratory culture blocked NMDA receptors. In this study, they confirmed through a series of experiments that the receptors for APOE and NMDA interacted, and that the protein that linked the two was PSD95, often found in neural synaptic junctions. Together, they form a multiprotein complex that could presumably be activated by either APOE, NMDA or glutamate.

Rebeck suspects that the APOE4 variant — the one linked to Alzheimer’s disease — is less efficient at removing lipid debris in the brain than is APOE2 or APOE3, and because of this, brain cells secrete more of the faulty protein to do the job. If too much APOE ends up binding to the APOE/NMDA receptor, one of two things could possibly happen, Rebeck says. In one scenario, the receptor becomes over-stimulated due to the accumulating presence of APOE, which could trigger a process called excitotoxicity that results in death of the neruons. Or, in the presence of damage and secreted APOE, the receptor “turns down” its activity — thus, hampering memory formation — until the brain is repaired. “Having damage around tells the brain not to think too much for awhile,” Rebeck says. But if APOE4 cannot clear up accumulating damage, the ability to make new memories, and use old ones, may be increasingly lost.

Hat tip to Medicineworld.
Original newsrelease source

Other researchers are on this fertile trail. Chang, Ma, et al from UC San Francisco published this intriguing article examining the molecular mechanisms of neurotoxicity and mitochondrial dysfunction. The researchers looked at variants of apoE4, to determine the precise portion of the peptide chain that was responsible for the toxicity.

ApoE4(241-272) did not cause mitochondrial dysfunction or neurotoxicity, suggesting that the lipid-binding region alone is insufficient for neurotoxicity. Truncation of N-terminal sequences (amino acids 1-170) containing the receptor-binding region (amino acids 135-150) and triple mutations within that region (R142A, K146A, and R147A) abolished the mitochondrial interaction and neurotoxicity of apoE4(1-272). Further analysis showed that the receptor-binding region is required for escape from the secretory pathway and that the lipid-binding region mediates mitochondrial interaction. Thus, the lipid- and receptor-binding regions in apoE4 fragments act together to cause mitochondrial dysfunction and neurotoxicity, which may be important in Alzheimer's disease pathogenesis.

The full text article is available here.

Ben Best has provided a useful description of the possible mechanisms of Alzheimer's Disease. In this section he discusses the apoE4 connection. A woman with one APOE4 allele has 4 times the AD risk of a woman with no APOE4 allele. A person with two APOE4 alleles has as much as 16 times the AD risk [INTERNATIONAL JOURNAL OF CLINICAL PRACTICE 56(3):197-203 (2002)].

In this article, I discussed a novel treatment for Alzheimer's, which is effective for both moderate and severe Alzheimer's Disease. Since the drug Memantine blocks NMDA receptors, and is a more effective treatment for AD than the earlier cholinesterase inhibiting drugs, it is clear that a more profound understanding of the actual mechanisms for AD will lead to even better treatments, even effective prevention methods.

Please understand that prevention of Alzheimer's will have a much more profound effect on society as a whole, than an effective treatment. By the time the disease is diagnosed, much damage may already have occurred.

Now that we better understand part of the genetic susceptibility for AD, more people will opt for an early genetic diagnosis. But what good is knowing that you are susceptible to early or late onset Alzheimer's if there is nothing you can do about it? Of course, Ben Best and others talk about preventing Alzheimer's with nutrients and vitamins. Curcumin is considered a likely preventative, given the very low incidence of Alzheimer's in India, where curried foods are commonly eaten daily.

The latest research by Rebeck et al, and Chang et al, are intriguing to me for another reason. They suggest that many of the symptoms of Alzheimer's patients may very well be reversible--not yet permanent. In other words, many of the NMDA receptors necessary for learning may simply be overwhelmed by excess debris, but not yet destroyed. That would partially explain why many AD patients are better on some days than others. Take away the damaging waste products, and the brain "sobers up" temporarily.

Would I have myself tested genetically? Why not? Research is advancing quickly. Until efficient pharmaceuticals for prevention of AD are approved, there is always Curcumin.

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