Figure 8.

The injurious response of Aβ, aka its failed “last ditch effort” to downregulate propagation of toxic tau and rebalance apoptotic-necrotic signaling dynamics. Due to accumulated toxic tau aggregates and dysregulated tau clearance by reactive astrocytes and microglia, pro-death signaling mechanisms become favored over cellular preservation signaling. However, a recurrent, reactive ER stress response leads to an imbalance of apoptotic-necrotic signaling and enhances atypical tau phosphorylation. Further, Aβ precursor protein is cleaved by caspase-3, and Aβ concentrations increase, further propagating the ER stress response (88, 154, 155). Due to the Aβ precursor overexpression and increased Aβ production, defective mitochondria are produced, mitochondrial dynamics are altered, and their trafficking is reduced, leading to further intracellular Ca²⁺ influx and apoptotic-necrotic imbalance (166). However, the ER stress response also has neuroprotective effects, inducing selective transcription factor XBP1, which mediates Aβ plaque formation (88). Simultaneously, Aβ directly recruits reactive astrocytes and indirectly recruits microglia, through TNF-α and pro-inflammatory signaling, which cluster around Aβ plaques to clear them (157, 167, 168). Yet, the induction of pro-inflammatory signaling from astrocytic recruitment further induces Aβ precursor protein; increased Aβ concentrations result in increased atypical tau phosphorylation/hyper-phosphorylation and further ER stress response induction (169). Thus, reactive astrocytes have both neuroprotective and injurious effects (170). Continued apoptotic-necrotic signaling imbalance, degradation in cell structure, and NFT formation results from atypical activation of these pathways. PERK, protein kinase R-like ER kinase; Aβ, amyloid beta; XBP1, X-box binding protein 1; TNF, tumor necrosis factor; IL, interleukin; Co-stim, co-stimulatory (molecules); Cyt-c, cytochrome-c; Apaf-1, apoptotic peptidase activating factor-1; dATP, deoxyadenosine triphosphate; NFTs, neurofibrillary tangles; Red = Pro-death signaling, Green = Neuroprotective signaling, Orange = Aβ-involved signaling; o-tau, tau oligomers; t-tau, total tau; p-tau, phosphorylated tau; *** = O-tau, t-tau, p-tau. X = reduction/down-regulation. Solid line = signaling cascade induced/propagated by the ER stress response and tau; dashed line = signaling cascades resulting from Aβ involvement.