Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel.
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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    ABSTRACT: Objective: We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods: Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results: No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions: The MTHFR 677C>T polymorphism--especially the presence of one copy of the T allele--appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.
    Disease markers 09/2013; 35(5):439. DOI:10.1155/2013/524106 · 1.56 Impact Factor
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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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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory deficits and death. While the number of individuals with AD is rising each year due to the longer life expectancy worldwide, current therapy can only somewhat relieve the symptoms of AD. There is no proven medication to cure or prevent the disease, possibly due to a lack of knowledge regarding the molecular mechanisms underlying disease pathogenesis. Most previous studies have accepted the "amyloid hypothesis," in which the neuropathogenesis of AD is believed to be triggered by the accumulation of the toxic amyloid beta (A β ) protein in the central nervous system (CNS). Lately, knowledge that may be critical to unraveling the hidden pathogenic pathway of AD has been revealed. This review concentrates on the toxicity of A β and the mechanism of accumulation of this toxic protein in the brain of individuals with AD and also summarizes recent advances in the study of these accumulation mechanisms together with the role of herbal medicines that could facilitate the development of more effective therapeutic and preventive strategies.
    Evidence-based Complementary and Alternative Medicine 05/2013; 2013(3):413808. DOI:10.1155/2013/413808 · 1.88 Impact Factor
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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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    ABSTRACT: Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.
    Cholesterol 10/2012; 2012(3):292598. DOI:10.1155/2012/292598
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