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: 2.26). 04/2005; 229-230:233-40. DOI: 10.1016/j.jns.2004.11.036
Source: PubMed

ABSTRACT 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.

  • Source
    [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.
    Disease markers 09/2013; 35(5):439. DOI:10.1155/2013/524106 · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; 2012:292598. DOI:10.1155/2012/292598
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant folded proteins are hallmarks of amyloidogenic diseases. Examples are Alzheimer's disease (AD) and prion-related disorders (PrD). These disorders, although clinically different, have the same underlying pathogenetic mechanism: an altered protein conformer with high β-sheet structure content: the amyloid beta peptide (Aβ) in the case of AD, and the aberrant prion protein, PrPsc in PrD. Although the molecular processes that cause these proteins to adopt non-native structures in vivo and become cytotoxic are still largely unknown, there is good reason to expect prion research to profit from advances in the understanding of AD, and vice versa. Growing evidence indicates that the various pathways of lipid/lipoprotein metabolism play a key role in AD and PrD pathophysiology. These findings clearly highlight the possible involvement of cholesterol in misfolded protein generation. In this review, we focus on recent studies which provide evidence that membrane domains, called lipid rafts, directly promote protein misfolding, and that this process takes place only if changes occur in the fine regulation of intracellular cholesterol. In addition, we discuss the implications of these results to introduce the concept that pharmacological interventions restoring cholesterol homeostasis could have potential preventive/therapeutic value against the progression of misfolding disorders. The aim of the review is to provide researchers with a general understanding of cholesterol's involvement in protein folding/misfolding processes which may be relevant for knowledge advancement regarding amyloidogenic proteins, and possible ways to prevent their pathological activity.
    Current Drug Targets 07/2010; 11(8):1018-1031. DOI:10.2174/138945010791591386 · 3.60 Impact Factor


1 Download