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.

Keywords: APP; Alzheimer’s disease; Aβ-clearance; Ca2+ dysregulation; ER-mitochondrial axis; autophagy; intracellular Aβ; molecular chaperones; neuroinflammation; protein and lipid dyshomeostasis.

Figure 1

Simplified presentation of the amyloid precursor protein (APP) and its processing products. Principal cleavage of APP with α-secretase results in the formation of water soluble products (SAPP-α, C83 and P3). Alternative (amyloidogenic) cleavage with β- and γ-secretase gives a heterogeneous mixture of β-amyloid (Aβ) peptides of 37 to 43 amino acids.

Figure 2

Schematic representation of the intracellular proteostasis network. Cytosolic misfolded proteins are bound by molecular chaperones, such as the HSPs. Molecular chaperones may act as aggregate unfolding and refolding enzymes. Autophagy pathways (chaperone-mediated, micro- and macroautophagy) degrade misfolded proteins. Ubiquitinated proteins are degraded by the ubiquitin-proteasome system. Sequestration of degraded misfolded proteins may form compact aggresomes and IPODs. Proteasome resistant aggresomes become enveloped by autophagosome membranes and transported into the lysosomes for autophagy.

Figure 3

Three signal pathways of ER-stress activate UPR. ER chaperone GRP78 under normal conditions binds all the three ER-stress sensors (PERK: protein kinase RNA like ER-kinase; IRE1α: inositol requiring enzyme 1α; ATF6: activating transcription factor 6). Under ER-stress GRP78 dissociates from sensors. PERK and IRE1α will be phosphorylated and oligomerized, ATF6 translocates to the Golgi (Abbreviations: eIF2α: eukaryotic translation initiation factor 2α; XBP1: X-box binding protein 1 (spliced form); TRAF2: TNF-associated factor-2; ATF4: transcriptional activator factor-4; MT: mitochondrium). ATF6, ATF4 and XBP1 activate UPR target genes to enhance the capacity of the ER to cope with unfolded proteins. Activation of Sig-1R inhibits the three branches of UPR.

Figure 4

Genes of high and low penetrance, as well as epigenetic and environmental factors are participating in AD pathogenesis. Brain traumas, vascular problems (cerebral hypoperfusion, hypoxia, hypoglycemia), declining amyloid degradation and clearance with aging are involved in ER- and mitochondrial dysfunction and protein dyshomeostasis. Amyloid accumulation leads to neuroinflammation, synaptic failure, neuronal dysfunction and death.