Alzheimers Disease: amyloid-beta and sticky plaques

I thought it would be fun to do a series on hot new trends in science and medicine based on different mechanisms of action, partly because this is what science is all about and partly because hearing about creative new scientific strategies gives me a sense of awe and wonder.

One idea that hit my mailbox today was a fascinating article on new targets for Alzheimers disease (AD) in SciBX, a Nature publication.  For a limited time the leading articles are downloadable free of charge.  You can find the link to the Alzheimers article here, which said:

"A study by a team at Genentech Inc proposes a new mechanism for Alzheimers disease pathogenesis by outlining a process that could be an early step in the neurogenerative disorder.  The work also identifies a trio of new AD targets, which the company is pursuing with preclinical programs." 

According to Genentech's website:

"Anti-Abeta is a humanized monoclonal antibody, which binds to amyloid beta (Abeta). Abeta is the main constituent of amyloid plaque in the brains of patients with Alzheimer's disease and is proposed to be causative in the development of the disease."

It has long been observed that Alzheimer's patients develop a build up of amyloid plaques and neurofibrillary tangles made of misfolded proteins in their brain.  The plaques are abnormal accumulations of sticky amyloid-beta protein between the neurons.  This situation arises when the amyloid precursor protein is incorrectly cut into pieces.  The tangles exist as a filamentous collection of twisted and hyperphosphorylated tau found in the cell body of a neuron.

The NIH has a beautiful illustration of the difference between a healthy and diseased neuron as well as other images on its website that are free to download:

A number of drugs have tried to slow the progression of the disease, with limited success.  Once the plaques and tangles have formed, it is difficult to effect any change in the disease.

Earlier this year Yale researchers reported that cellular proteins called prions activate the process by which amyloid-beta peptides impair brain function in people with the disease.  Cellular prion proteins are usually harmless and exist in all cells, but they can change shape and cause disease.  Essentially, in Alzheimer's, they appear to start the cascade that makes the neurons sick.

These concepts raise several questions - can the amyloid plaques be stopped or slowed down from developing or can they be eliminated or reversed in some way.

The study by the Genentech team, which was reported in Nature, suggests a new mechanism for the pathogenesis of Alzheimer's disease by outlining a process that could be an early step in the neurodegenerative disorder. 

The work also identifies a trio of new AD targets, which the company is pursuing with preclinical programs. The study suggests that the previously ignored amino-terminal portion of amyloid precursor protein (APP), called N-APP, might be the main culprit behind AD.  APP is a transmembrane protein that gives rise to N-APP and the much more commonly known amyloid (A), a fragment that forms the amyloid fibres and plaques that are hallmarks of AD, although the precise role of these in the disease pathology is unclear.  A schematic is shown below, from the Nature article:

Of course, none of this new research is going to help those of us who are struggling with parents with AD, but perhaps by the time we are seniors there will be some improvements in available therapies and earlier detection of this devastating disease.  There is some justification for that raised hope because a newly discovered mutation, the A673V mutation, is associated with familial AD.  The inheritance pattern is recessive, meaning a patient needs two mutant alleles in order to acquire the disease risk.  This is unusual because most AD is sporadic and not inherited.

Regular readers of this blog will be familiar with wild type and mutant mutations seen in cancer conferring different prognosis.  It seems that they also appear in AD.  Interestingly, in combination with wild type allele, A673V doesn’t cause AD.  The presence of mutant protein prevents the wild type protein from forming amyloid fibrils, even under very favorable in vitro conditions.

As we learn more about the biology of Alzheimers Disease, hopefully new and better treatments will be developed.  Perhaps we might even understand one day what actually causes or triggers the disease to begin it long slow process in the first place.  Now that would be something.

Osherovich, L. (2009). Genentech's new parADigm Science-Business eXchange, 2 (8), 1-5 DOI: 10.1038/scibx.2009.300

Di Fede, G., Catania, M., Morbin, M., Rossi, G., Suardi, S., Mazzoleni, G., Merlin, M., Giovagnoli, A., Prioni, S., Erbetta, A., Falcone, C., Gobbi, M., Colombo, L., Bastone, A., Beeg, M., Manzoni, C., Francescucci, B., Spagnoli, A., Cantu, L., Del Favero, E., Levy, E., Salmona, M., & Tagliavini, F. (2009). A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis Science, 323 (5920), 1473-1477 DOI: 10.1126/science.1168979

Related articles by Zemanta

• Prions Involved in Some Alzheimer's (sciam.com)
• Scientists Spot New Clue to Alzheimer's (nlm.nih.gov)
• Drug offers hope on Alzheimer's (news.bbc.co.uk)
• links for 2009-05-12 (pharmastrategyblog.com)

Comments

[Dental Lake Worth]

Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.