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Cholesterol, Statins, and Alzheimer's disease

Posted by plosmedicine on 30 Mar 2009 at 23:39 GMT

Author: Alexei R. Koudinov
Position: neuroscientist, editor
Institution: Neurobiology of Lipids, http://neurobiologyoflipi... Russian Academy of Medical Sciences
Additional Authors: Temirbolat T. Berezov
Submitted Date: January 16, 2005
Published Date: January 24, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

After reading excellent Research Article by Pedrini et al (PLoS Medicine, 10.1371/journal.pmed.0020018) and associated Synopsis (PLoS Medicine, 10.1371/journal.pmed.0020022) one may conclude that the only pathway of statins effect on Alzheimer's disease (AD) is the regulation of amyloid precursor protein (APP) processing and amyloid beta protein (Ab) generation. The moderation is provided in Research Article Patient Summary, reminding that "statins are likely to influence the risk for Alzheimer disease by several different pathways." What are these other pathways? It is essential to note, that in addition to APP processing and Ab chemistry, modulated by statins fine tuning of cholesterol homeostasis affects cholinergic function, ionotropic and metabotropic receptors, tau phosphorylation, neural oxidative stress reactions, and other features of neurodegeneration (reviewed in J Neurological Sciences, doi:10.1016/j.jns.2004.11.036). Moreover, precise regulation of neural cholesterol dynamics and supply is itself essential for synapse function, plasticity, behaviour (ibid). These data suggest that in addition to sporadic AD, cholesterol homeostasis break is the unifying primary cause of neuromuscular diseases, Niemann-Pick's type C disease and Down syndrome, and formulate why rare cases of familial AD (associated with mutations in APP and presenilin genes), are translated into the Alzheimer's via membrane cholesterol sensitivity of APP processing by secretases and Ab generation. Also important, is the Synopsis' apparently outdated dividing of APP processing on "harmful" (Ab-generating) and "healthy" (non-amyloidogenic). One should be cautious to call Ab a harmful molecule. This is because several recent studies illuminated essential function for amyloidogenic processing of APP and Ab in neurons (J Neurosci. 2003 Jul;23(13):5531-5) and synapses (Neuron 2003 Mar;37(6):925-37). In this context, the reciprocal effect of Ab on cholesterol synthesis, cellular uptake, efflux, esterification, and its' relation to the experimental restoration of long-term potentiation (LTP, a synaptic plasticity measure) may represent one of the poorly comprehend physiological functions of Ab (Neurobiol Lipids, 2003 Sept;2:8).

Competing interests declared: Alexei Koudinov serves as founding and managing editor of the Neurobiology of Lipids (ISSN 1683-5506), an unpaid position. We declare that we have no competing financial interests.