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.
Highlights
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder associated with dementia, and the progressive deterioration of mental capacities
One of the events that promotes AD pathogenesis is the abnormal processing of amyloid precursor protein (APP), which leads to excess production of amyloid β (Aβ) peptides through the sequential enzymatic actions of beta-site APP cleaving enzyme 1 (BACE1), a β-secretase, and γ-secretase, both enzymes of the amiloidogenic pathway
While Aβ has been widely demonstrated to be pro-inflammatory, the association between microglial activation and tau pathology development is still not supported by direct evidence, since neurofibrillary disorder occurs both in the presence and absence of neuroinflammation (Streit et al, 2014), and intraneuronal neurofibrillary tangles (NFT) lesions usually precede the formation of Aβ aggregates (Braak and Del Tredici, 2004)
Summary
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder associated with dementia, and the progressive deterioration of mental capacities It is a complex disease characterized by progressive memory impairment, cognitive deficit, and personality changes; these symptoms are due to substantial synaptic and neuronal loss occuring in specific brain areas, especially in the neocortex, hippocampus, and other subcortical regions. Environmental factors increase the risk of AD, this disease can be caused by various gene mutations (Gatz et al, 2006) In this contest, mutation in the genes APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) accounts for most cases of the familial (or early-onset) form of AD, by increasing the production and aggregation of Aβ and amyloid plaque formation (Tanzi and Bertram, 2005). The pathophysiology of AD is still not clearly understood, considerable evidence indicates that many events participate in the development and progression of the disease, including oxidative stress, inflammation, glial cell activation, dysregulation of metal ions and calcium, presence of ApoEε4, altered cholesterol metabolism, and dysregulation of intercellular communication among brain cells (Quintanilla et al, 2012)
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