Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.
We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD.
Koudinov
Alexei R
AR
Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel. alexeikoudinov@neurobiologyoflipids.org
Koudinova
Natalia V
NV
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009473:Neuronal Plasticity / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides; D002784:Cholesterol