Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Russian Academy of Medical Sciences, Moskva, Moscow, Russia
Journal of the Neurological Sciences (Impact Factor: 2.47). 04/2005; 229-230:233-40. DOI: 10.1016/j.jns.2004.11.036
Source: PubMed


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.

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    • "It has been shown that animals fed a diet supplemented with 2% cholesterol have increased Aí µí»½ in the brain cortex and hippocampus. Furthermore, impaired brain cholesterol dynamics have been described as a potential cause of AD [19]. Despite the weight of genetic information on AD, only a few reports provide evidence on genetic-biochemical interactions that affect the risk of AD. "
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    • "However, neuronal cells seem to generate greater amounts of Aβ than other cell types [16], indicating that the Aβ peptide might play an important role in the normal physiology of the CNS. There is a notion that Aβ might serve as an essential synaptic protein in synaptic structural-functional plasticity underlying learning and memory, an idea supported by the increased long-term potentiation mediated by Aβ40 (LTP) [18]. Therefore, the neuropathological events occurring in individuals with AD likely result from the toxicity of amyloid oligomers and fibrils, which are the aggregated forms of Aβ, rather than from its monomeric form. "
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    • "Cholesterol is required for synapse and dendrite formation [4] [5], and for axonal guidance [6]. Cholesterol depletion leads to synaptic and dendritic spine degeneration, failed neurotransmission, and decreased synaptic plasticity [7]. Cholesterol is a pivotal constituent of cell membranes, steroid hormones, and for the function of the hedgehog protein [8]. "
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