Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of β-amyloid (Aβ) and neurofibrillary tangles (NFTs). Apart from Aβ and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, “surveying” phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aβ plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aβ plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for in silico drug screening and gains further insight into the development of microglia-based therapeutic interventions for AD.

Studies on the mechanism of Toxoplasma gondii Chinese 1 genotype Wh6 strain causing mice abnormal cognitive behavior

“…There is some clear evidence that the inflammatory response of microglia is part of the vital pathogenesis of AD [ 38 ]. To ascertain the effect of microglia infected by TgCtwh6 on neurons, we first explored in vitro the mechanism with which the TgCtwh6 tachyzoites induce BV2 polarization.…”

Circular RNAs: New players involved in the regulation of cognition and cognitive diseases

“…Similarly, using Aβ-treated SK-N-SH and SK-SY5Y cell lines, a study suggested that circRNA AXL increased neuronal injury and inflammation by targeting microRNA-328-mediated BACE1 in AD ( Li Y. et al, 2022 ). The presence of Aβ and NFTs promotes microglial cell activation, leading to a persistent and robust release of inflammatory cytokines and chemokines and finally the death of surrounding neurons ( Agrawal and Jha, 2020 ; Perea et al, 2020 ; Xu Y. et al, 2022 ). In a microglial cell line, BV2 cells, knockdown of circ_0005835 downregulated neuroinflammation by sponging miR-576-3p and changed the process of AD ( Xu X. et al, 2022 ).…”

Neuroinflammation of microglia polarization in intracerebral hemorrhage and its potential targets for intervention

“…Interestingly, a transcriptomic framework of microglial activation uncovered that DAM demonstrates double anti-inflammatory and pro-inflammatory sub-profiles in (AD and aging models; Rangaraju et al, 2018 ; Gao et al, 2019 ). The progressive transition from homeostatic microglia to reactive DAM relies on TREM2, which is mainly located on the microglia surface in brain tissue (Arcuri et al, 2017 ; Mecca et al, 2018 ; Xu et al, 2022 ). The activated TREM2 alleviated microglia neuroinflammation, neurological deficits, and neuronal loss by activating the PI3K/Akt signaling pathway in perihematomal areas following ICH (Chen et al, 2020 ).…”