Deciphering Alzheimer Disease

Abstract

Alzheimer disease represents an insidious impairment of intellect and emotional well-being. However, recent advances in biochemical pathology and human genetics offer promise that effective therapeutic agents may soon be developed.

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

“…A number of studies have reported biophysical features, environmental conditions, and molecular partners that promote or repress the initial aggregation of specific proteins (1,3,7,(13)(14)(15). More recently, it has been recognized that the regulation of many other proteins is disrupted as a consequence of these initial aggregation events (8,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

“…More generally, however, it is clear that AD belongs to a class of protein conformational disorders whose characteristic feature is that specific peptides and proteins misfold and aggregate to form amyloid assemblies (1,3,6). The presence of such aberrant aggregate species generates a cascade of pathological events, leading to the loss of the ability of protein homeostasis mechanisms to preserve normal biological function and to avoid the formation of toxic species (1,3,6).…”

“…lzheimer's disease (AD) is a neurodegenerative condition responsible for the majority of reported cases of dementia, affecting over 44 million people worldwide (1)(2)(3)(4)(5)(6). Although the exact nature of this disease has not been defined fully, its onset and progression have been associated with a multitude of factors, including mitochondrial dysfunction, disruption of the endoplasmic reticulum and membrane trafficking, disturbances in protein folding and clearance, and the activation of the inflammatory response (1)(2)(3)(4)(5)(6).…”

“…Although the exact nature of this disease has not been defined fully, its onset and progression have been associated with a multitude of factors, including mitochondrial dysfunction, disruption of the endoplasmic reticulum and membrane trafficking, disturbances in protein folding and clearance, and the activation of the inflammatory response (1)(2)(3)(4)(5)(6). More generally, however, it is clear that AD belongs to a class of protein conformational disorders whose characteristic feature is that specific peptides and proteins misfold and aggregate to form amyloid assemblies (1,3,6). The presence of such aberrant aggregate species generates a cascade of pathological events, leading to the loss of the ability of protein homeostasis mechanisms to preserve normal biological function and to avoid the formation of toxic species (1,3,6).…”

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

“…Pathologically, AD is characterized by the accumulation of 38 -43-amino acid-long amyloid ␤ peptides (A␤) in senile plaques and the presence of tangles composed of hyperphosphorylated tau in the brains of affected individuals (2). Clinically, Ͼ90% of cases of AD are classified as non-familial or sporadic disease, with aging as the main risk factor.…”