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

Abstract

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 Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ 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 Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research.

The trans-Golgi network is a major site for α-secretase processing of amyloid precursor protein in primary neurons

“…Under physiological conditions, the nonamyloidogenic and amyloidogenic processing pathways of APP are considered to represent the major and minor pathway in cells, respectively (6,37). The cleavage and shedding of the luminal, or ecto, domain of APP by the metalloprotease ␣-secretase is a key processing event, as it is considered to minimize the generation of the pathogenic A␤ peptides associated with Alzheimer's disease (38,39).…”

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…Amyloid‐beta is generated from the larger precursor protein amyloid precursor protein (APP) through proteolysis. Proteolytic enzymes involved in amyloid‐beta generation (i.e., the amyloidogenic pathway) include beta‐secretase (BACE) and gamma‐secretase complex (Moussa‐Pacha, Abdin, Omar, Alniss, & Al‐Tel, ; Penke, Bogár, & Fülöp, ). Amyloid‐beta can be removed through a proteolytic catabolism pathway.…”

Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells

“…AD has become a critical issue in human health globally and accounts for 70% of dementia in patients (Martins et al, ). The amyloid precursor protein (APP) is a molecule central to the amyloid hypothesis which states that APP is cleaved by secretase to form toxic amyloid‐β (Aβ) peptides and plaques leading to AD (Hardy & Higgins, ; Penke, Bogár, & Fülöp, ). Constitutive mutations and duplications in the APP gene are found to cause rare forms of familial AD, its pathology in Down syndrome, or increased gene recombination by multiple APP variants in the neurons of patients with AD, indicating a pathological role of APP in the development of AD (Götz, Matamales, Götz, Ittner, & Eckert, ; Hardy & Selkoe, ; Lee et al, , Murrell, Farlow, Ghetti, Benson, ).…”

“…Constitutive mutations and duplications in the APP gene are found to cause rare forms of familial AD, its pathology in Down syndrome, or increased gene recombination by multiple APP variants in the neurons of patients with AD, indicating a pathological role of APP in the development of AD (Götz, Matamales, Götz, Ittner, & Eckert, ; Hardy & Selkoe, ; Lee et al, , Murrell, Farlow, Ghetti, Benson, ). Regulation of APP cleavage is usually dependent on the secretase activity (Penke et al, ). APP is sequentially cleaved by the protease β‐secretase 1 which binds to the β‐sites of APP, and the γ‐secretase/presenilin complex present at its γ‐sites forming Aβ peptides in the amyloidogenic pathway (Lei & Renyuan, ; Penke et al, ).…”