Neurochemical Aspects of Alzheimer's Disease

Neurochemical Aspects of Alzheimer's Disease

Risk Factors, Pathogenesis, Biomarkers, and Potential Treatment Strategies
2017, Pages 1-46
Neurochemical Aspects of Alzheimer's Disease

Chapter 1 - Neurochemical Aspects of β-Amyloid Cascade Hypothesis for Alzheimer’s Disease: A Critical Evaluation

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Abstract

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder that causes severe impairment of cognitive function, leading to a drastic decline in the quality of life. Neuropathological features of AD include the accumulation of β-amyloid (Aβ) and deposition of extracellular senile plaques and accumulation of intraneuronal tangles that consist of aggregated and hyperphosphorylated Tau protein. According to the Aβ cascade hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). These hallmarks are accompanied by oligomerized soluble Aβ [Aβ-derived diffusible ligands (ADDL)]-mediated loss of neurons, ADDL-mediated impairment of neuronal functions, synaptic dysfunction, onset of oxidative stress, induction of neuroinflammation, loss of Ca2+ homeostasis, and brain atrophy. Less than 5% of AD cases are of genetic origin (familial) and are caused by mutations in the APP gene or genes [APP, presenilin 1 (PSEN1), PSEN2, and APOE] that affect amyloid processing. The vast majority of AD cases are sporadic and characterized by late onset. Recent studies indicate that a direct correlation between ADDL and dementia severity has not been clearly established, since some patients without amyloid deposition show severe memory deficits, whereas other patients with cortical Aβ deposits have no dementia symptoms. These observations along with the failure of some anti-Aβ therapies to preserve or rescue cognitive function suggest that Aβ may not be the only neurotoxin but that other mechanisms (activation of kinases, modulation of cholesterol transport, or alterations in neural membranes) may also contribute to the pathogenesis of AD.

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