Microglial autophagy in Alzheimer's disease and Parkinson's disease

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, characterized by gradual and selective loss of neurons in the central nervous system. They affect more than 50 million people worldwide, and their incidence increases with age. Although most cases of AD and PD are sporadic, some are caused by genetic mutations that are inherited. Both sporadic and familial cases display complex neuropathology and represent the most perplexing neurological disorders. Because of the undefined pathogenesis and complex clinical manifestations, there is still no effective treatment for both AD and PD. Understanding the pathogenesis of these important neurodegenerative diseases is important for developing successful therapies. Increasing evidence suggests that microglial autophagy is associated with the pathogenesis of AD and PD, and its dysfunction has been implicated in disease progression. In this review, we focus on the autophagy function in microglia and its dysfunction in AD and PD disease models in an attempt to help our understanding of the pathogenesis and identifying new therapeutic targets of AD and PD.

Keywords: AD; PD; autophagy; microglia; neurodegeneration.

Figure 1

The mechanisms by which microglia respond to aggregated proteins. Firstly, aggregates (Aβ/Tau/α-syn) are recognized by microglial pattern recognition receptors, such as TLR2 and TLR4. Afterward, these receptor binding activates the specific signaling pathways involving MYD88/NF-κB, which leads to transcription of NLRP3 and subsequent enables the release of inflammatory cytokines, namely IL-18 and IL-β. Further, the release of cytokines will induce chronic inflammatory responses.

Figure 2

The mechanism of microglial synucleinphagy. Microglia ingest extracellular α-syn protein, which is sequestered by the autophagy-lysosome pathway. This process is mediated through TLR4-NF-κB signaling, and leads to the endocytosis- and phago-independent ingestion of extracellular α-syn. In this process, α-syn-TLR4 interaction stimulates p62 expression mediated by NF-κB. Meanwhile, α-syn can enter the cells or penetrate cytoplasmic membrane through other endocytosis-independent processes [such as lipid raft (Park et al., 2009)] or endocytosis-dependent processes (Lee et al., 2008a). Then, oligomeric p62 binds and recruits ubiquitinated-α-Syn (Ub-α-Syn) into autophagosomes for degradation.