The underlying molecular mechanisms that cause the formation of the hallmarks of FAD and SAD, namely, amyloid- β- (A β-) containing plaques and microtubule-associated protein tau-containing neurofibrillary tangles (NFTs), are not yet fully clarified. While one out of nine people aged 65 or older has Alzheimer's, nearly one out of three people aged 85 or older has the disease. Sporadic, or late-onset, AD (SAD) which is a major form (over 95% of cases) has unknown etiology. Early-onset familial AD (FAD) which accounts for less than 5% of cases is linked to mutations in APP gene on chromosome 21 or genes encoding components of γ-secretase (presenilin 1, presenilin 2) resulting in increased A β 42/40 ratio, where A β 42 is highly fibrillogenic. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.Īlzheimer's disease (AD) is known for almost 120 years as a progressive fatal human neurodegenerative disease featured by decline in both memory and cognitive functions.
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Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Besides, APP, A β, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Similarly, without obvious reasons, the passage of A β and tau to mitochondria is observed. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD.
The origin and consecutive fate of APP, A β, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, A β, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD.
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