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. 2024 Jan 5;14:1287545. doi: 10.3389/fneur.2023.1287545

Figure 6.

Figure 6

The neuroprotective response of Aβ, aka the “last ditch effort” to revert the cell to programmed death signaling and rebalance the apoptotic-necrotic signaling dynamic. In response to a recurrent or sustained ER stress response, imbalanced apoptotic-necrotic signaling dynamic, and atypical tau phosphorylation, Aβ activation both induces the ER stress response and increases caspase-3 cleavage of Aβ precursor protein (155). However, Aβ also recruits microglia and reactive astrocytes in response to excitotoxic signaling and increased tau concentrations (156). Breakdown of toxic tau aggregates and Aβ by microglia and reactive astrocytes mitigates the effect of Aβ-associated tau seeding and propagation (133, 157). As increased microglial trafficking is indirectly induced by the presence of Aβ, this mechanism also has detrimental effects due to shared apolipoprotein E (APOE), amyloidosis, and microglial transcript pathways and sustained neuroinflammation (158). Due to microglial inflammation and activation, reactive astrocytes are upregulated and recruited in attempts to clear toxic tau and Aβ and further orient the cell toward apoptotic signaling (159–162). Ultimately, a reduction in both inflammatory signaling and tau phosphorylation are needed once apoptotic-necrotic signaling dynamics have been reestablished, to prevent transition to an irreversible, degenerative pathway. 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.