Dyslipidemia and the Risk of Alzheimer's Disease.
ABSTRACT Whether cholesterol is implicated in the pathogenesis of Alzheimer's disease (AD) is still controversial. Several studies that explored the association between lipids and/or lipid-lowering treatment and AD indicate a harmful effect of dyslipidemia on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E (APOE), apolipoprotein J (APOJ, CLU), ATP-binding cassette subfamily A member 7(ABCA7), and sortilin-related receptor (SORL1). Functional cell biology studies further support a critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase resulting in altered Aβ production. However, conflicting evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, randomized clinical trials observing no beneficial effect of statin therapy, and cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol level is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits colocalization of β-secretase 1 and Aβ precursor protein in nonraft membrane domains, thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this article is to provide a comprehensive review of the findings of epidemiological, genetic, and cell biology studies aiming to elucidate the role of cholesterol in the pathogenesis of AD.
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- "In this review, the major neuropsychiatric and behavioral symptoms of AD are reviewed with emphasis on how these symptoms may illuminate disease pathogenesis or provide prognostic information. Alzheimer's dementia is the end result of multiple pathogenic processes including aberrant amyloid processing  , changes in lipid metabolism due to apolipoprotein E (APOE) risk alleles  , tau hyperphosphorylation , protein misfolding and endoplasmic reticulum (ER) stress , vascular dysfunction , oxidative stress and mitochondrial dysfunction  , neurotrophic factor dysregulation , disrupted leptin signaling , fibrin clots , and processes mediated by a myriad of other AD-associated gene , and the pathogenic processes also occurred in major neuropsychiatric symptoms (Figure 1). It is likely that these processes target nonoverlapping neural networks, accounting for difference in disease progression and the variability in neuropsychiatric symptoms. "
ABSTRACT: Neuropsychiatric symptoms (NPS) such as depression, apathy, aggression, and psychosis are now recognized as core features of Alzheimer's disease (AD), and there is a general consensus that greater symptom severity is predictive of faster cognitive decline, loss of independence, and even shorter survival. Whether these symptoms result from the same pathogenic processes responsible for cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear. Many structural and metabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters. In addition, many genes have been identified and confirmed that are associated with symptom risk in a few cases. However, there are no single genes strongly predictive of individual neuropsychiatric syndromes, while functional and structural brain changes unique to specific symptoms may reflect variability in progression of the same pathological processes. Unfortunately, treatment success for these psychiatric symptoms may be lower when comorbid with AD, underscoring the importance of future research on their pathobiology and treatment. This review summarizes some of the most salient aspects of NPS pathogenesis.BioMed Research International 07/2014; 2014:927804. DOI:10.1155/2014/927804 · 2.71 Impact Factor
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ABSTRACT: The collective properties of the lipids that form biological membranes give rise to a very high level of lateral organization within the membranes. Lipid-driven membrane organization allows the segregation of membrane-associated components into specific lipid rafts, which function as dynamic platforms for signal transduction, protein processing, and membrane turnover. A number of events essential for the functional integrity of the nervous system occur in lipid rafts and depend on lipid raft organization. Alterations of lipid composition that lead to abnormal lipid raft organization and consequent deregulation of lipid raft-dependent signaling are often associated with neurodegenerative diseases. The amyloidogenic processing of proteins involved in the pathogenesis of major nervous system diseases, including Alzheimer's disease and Parkinson's disease, requires lipid raft-dependent compartmentalization at the membrane level. Improved understanding of the forces that control lipid raft organization will facilitate the development of novel strategies for the effective prevention and treatment of neurodegenerative and age-related brain diseases.Molecular Neurobiology 12/2013; 50(1). DOI:10.1007/s12035-013-8614-4 · 5.29 Impact Factor
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ABSTRACT: Effect of different meditation practices on various aspects of mental and physical health is receiving growing attention. The present paper reviews evidence on the effects of several mediation practices on cognitive functions in the context of aging and neurodegenerative diseases. The effect of meditation in this area is still poorly explored. Seven studies were detected through the databases search, which explores the effect of meditation on attention, memory, executive functions, and other miscellaneous measures of cognition in a sample of older people and people suffering from neurodegenerative diseases. Overall, reviewed studies suggested a positive effect of meditation techniques, particularly in the area of attention, as well as memory, verbal fluency, and cognitive flexibility. These findings are discussed in the context of MRI studies suggesting structural correlates of the effects. Meditation can be a potentially suitable non-pharmacological intervention aimed at the prevention of cognitive decline in the elderly. However, the conclusions of these studies are limited by their methodological flaws and differences of various types of meditation techniques. Further research in this direction could help to verify the validity of the findings and clarify the problematic aspects.Frontiers in Behavioral Neuroscience 01/2014; 8:17. DOI:10.3389/fnbeh.2014.00017 · 4.16 Impact Factor