Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease

Abstract

Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

Keywords: Alzheimer's disease; amyloid-β; interaction; phosphorylation; tau.

Figure 1

Tau phosphorylation sites and associated kinases. The identified tau phosphorylation sites are located in the N-terminal region (Ser46 , Thr123 , Ser198, Ser199, Ser202, Ser208, Ser210, Thr212, Ser214, Thr217, Thr231, and Ser235), the repeat region (Ser262 and Ser356), and the C-terminal region (Ser396, Ser400, Thr403, Ser404, Ser409, Ser412, Ser413, and Ser422 18). Ser199, Ser202, Thr231, Ser235, Ser262, Ser396, and Ser404 are phosphorylated by various activated kinases, namely A-kinase, C-kinase, CaM kinase II, CDK-5 and Gsk-3β, and Ser356 is phosphorylated by C-kinase, CaM kinase II, CDK-5 and Gsk-3β. A-kinase, C-kinase, CaM kinase II and CDK-5 are primarily involved in the prephosphorylation of tau. This prephosphorylation increases the affinity of GSK-3β to these sites, which ultimately leads to tau hyperphosphorylation.

Figure 2

Reciprocal toxicity between Aβ and tau. Aβ precursor protein (APP) is cleaved by β/γ secretases to form Aβ. Aβ activates GSK-3β and CDK-5 to phosphorylate tau protein and activate caspase-3 and calpain 1 to hydrolyse tau protein and form tau oligomers. Phosphorylated tau protein interacts with Fyn. Aβ-activated Fyn also accelerates tau phosphorylation and binds to tau. Phosphorylated Fyn acts on NR2B to form the NMDAR-PSD95-Fyn complex. NMDARs are activated to increase Ca²⁺, which affects the function of mitochondria. Aβ and phosphorylated tau induce the fusion and fission of mitochondria by acting on Drp1, which induces the dysfunction of mitochondrial dynamics and ultimately leads to reactive oxygen species (ROS) overproduction and apoptosis.

Figure 3

Interaction of Aβ and tau with microglia and astrocytes. In response to Aβ or tau, microglia and astrocytes are converted into a reactive state, which triggers the inflammatory cascade. These cells reciprocally activate each other via this cascade, which leads to neuronal injury. Inflammatory cytokines (such as interleukin-1β and TNF-α) induce the neuronal release of tau, and activated microglia take up extracellular tau. Cytokines also accelerate tau phosphorylation to ultimately induce the formation of neurofibrillary tangles (NFTs). Transcription factor EB (TFEB) activates astrocytes to take up extracellular tau. This process consists of a cycle of Aβ deposition, tau phosphorylation, release and uptake, and the roles of cytokines to ultimately lead to cell death and the NFT-mediated exacerbation of neurodegenerative changes.