Fig. 1

A model for Aβ-induced neurotoxicity and glial response in AD. a APP processing and Aβ generation. Aβ is generated by APP cleavage in acidified compartments such as late endosomes, and subsequently released from neurons. Extracellular Aβ sequentially assemble into Aβ oligomer aggregates (oAβ), fibrils, and ultimately amyloid plaques. b Aβ-mediated neuronal dysfunction. oAβ can disrupt synaptic function through LTP impairment and LTD enhancement. A variety of potential neuronal Aβ receptors such as EphA4, PrPc, EphB2, NMDAR, and LiLRB2 have been shown to bind Aβ and transduce synaptotoxicity. SORLA can inhibit EphA4-mediated synaptic and cognitive dysfunction with oAβ exposure. Fyn kinase is an important regulator for NMDAR-mediated oAβ neurotoxicity. oAβ also can alter mitochondria function to induce caspase-3 activation, ATP reduction and ROS upregulation, thereby aggravating synaptic dysfunction. c Effects of Aβ on microglia. oAβ may activate microglia through binding to the putative Aβ receptors such as TREM2, LRP1, RAGE, TLR4 and CD36. Specifically, the binding of Aβ to TREM2 activates SYK pathway through DAP12, an adaptor protein for TREM2, and leads to the degradation of Aβ. d Aβ-dependent microglia/astrocyte interactions, and Aβ-mediated astrocyte dysfunction. APOE released from the astrocytes binds Aβ, which enhances Aβ/APOE interactions with LRP1. Activated microglia release proinflammatory such as TNF-α, IL-1β, IL-6 and IL-8, which can activate astrocytes. In addition, oAβ can potentially activate astrocytes directly through α7-nAchR, CaSR, CD36, CD47 and AQP4. Activated astrocytes may damage neurons through extracellular glutamate dyshomeostasis/excitotoxicity, TNF-α, IL-1β and IL-6