Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

Keywords: Alzheimer’s disease; Astrocyte; Aβ; Microglia; Tau.

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

Fig. 2

A model for tau pathogenesis. a Tau is a microtubule-binding protein, which can undergo various types of post-translational modifications (PTMs), such as phosphorylation and truncation. Under disease conditions, aberrant PTMs induces tau dissociation from microtubules, leading to tau aggregation and oligomer formation. Tau oligomers can further aggregate to form PHFs and NFTs in neurons. Tau aggregates can induce mitochondria fragmentation, impair synaptic vesicle mobility and release, thereby leading to presynaptic dysfunction. In addition, pathological tau species such as truncated tau and tau oligomers can be released to the extracellular environment via exosomes or directly from the plasma membrane. b Tau is normally distributed to compartments other than postsynaptic densities. Hyperphosphorylated and truncated tau species may enter postsynaptic compartments to consequently impair LTP by modulating Fyn/NMDAR complexes. Extracellular pathogenic tau species may be internalized in neurons through a HSPGs-mediated pathway to induce the aggregation of intracellular tau. c Extracellular tau can bind CX3CR1 receptors, and subsequently internalized by microglia for degradation. Alternatively, tau released from neurons can enter microglia through unknown mechanisms. Internalized tau may be modified and re-released from microglia to the extracellular space via exosomes, and then taken up by adjacent neurons to induce tau propagation. In addition, pathological tau species can activate microglial NF-κB and NLRP3 inflammasome pathways, leading to pro-inflammatory cytokine release. Excessive pro-inflammatory cytokines can increase the activity of tau kinases such as CDK5 and P38, thereby exacerbating tau hyperphosphorylation