Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

ArticleinJournal of the Neurological Sciences 229-230:233-40 · April 2005with4 Reads
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.
    • "It has also been reported that Aβ fibrils down-regulate cholesterol metabolism in cultured neurons (Gong et al., 2002). Additionally, the intracellular domain of APP, which is released upon γ-secretase cleavage of APP, may act as a transcriptional suppressor of LRP1, leading to the down-regulation of cellular cholesterol uptake (Liu et al., 2007) and synaptic failure (Koudinov and Koudinova, 2005), as well as enhancement of tau phosphorylation (Fan et al., 2001). It has also been shown that extracellular cholesterol accumulates in the senile plaques of AD patients, and in transgenic mice expressing the Swedish Alzheimer mutation APP751, by binding to aggregated Aβ (Mori et al., 2001). "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain's high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes. The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier (BBB). The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death. This review highlights the key role played by cholesterol and oxysterols in the brain in AD pathogenesis.
    Full-text · Article · Jun 2015
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Sep 2013
    • "It has been also reported that the interaction of pre-fibrillar aggregates with the cell membrane is impaired when the membrane is enriched in cholesterol (reviewed in [29] ). Moreover, a higher membrane rigidity following increased cholesterol can be protective against any perturbation of membrane integrity and cell demise following aggregate growth at, or interaction with, the cell membrane [126,128,129]. Since Aβ toxicity is associated with the aggregation state of the peptide, many studies have investigated the cholesterol–Aβ toxicity relation. "
    [Show abstract] [Hide abstract] ABSTRACT: Amyloid cytotoxicity, structure and polymorphisms are themes of increasing importance. Present knowledge considers any peptide/protein able to undergo misfolding and aggregation generating intrinsically cytotoxic amyloids. It also describes growth and structure of amyloid fibrils and their possible disassembly, whereas reduced information is available on oligomer structure. Recent research has highlighted the importance of the environmental conditions as determinants of the amyloid polymorphisms and cytotoxicity. Another body of evidence describes chemical or biological surfaces as key sites of protein misfolding and aggregation or of interaction with amyloids and the resulting biochemical modifications inducing cell functional/viability impairment. In particular, the membrane lipid composition appears to modulate cell response to toxic amyloids, thus contributing to explain the variable vulnerability to the same amyloids of different cell types. Finally, a recent view describes amyloid toxicity as an emerging property dependent on a complex interplay between the biophysical features of early aggregates and the interacting cell membranes taken as a whole system.
    Full-text · Article · Jun 2013
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