β-Amyloid and the Pathomechanisms of Alzheimer's Disease: A Comprehensive View

Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer's disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic A beta aggregates (beta-amyloids). Protein folding is the basis of life and death. Intracellular A beta affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca2+-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the A beta-clearance from brain-to-blood decreases. Microglia-mediated clearance of A beta also declines, A beta accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research.