All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer’s disease

Abstract

In recent years, glial cells have been acknowledged as key players in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative condition in which an accumulation of intracellular neurofibrillary tangles and extracellular fibrillar amyloid beta is notably observed in the central nervous system. Genome-wide association studies have shown, both in microglia and astrocytes, an increase in gene variants associated with a higher risk of developing late-onset AD. Microglia, the resident innate immune cells of the brain, and astrocytes, glial cells crucial for vascular integrity and neuronal support, both agglomerate near amyloid beta plaques and dystrophic neurites where they participate in the elimination of these harmful parenchymal elements. However, their role in AD pathogenesis has been challenging to resolve due to the highly heterogeneous nature of these cell populations, i.e., their molecular, morphological, and ultrastructural diversity, together with their ever-changing responsiveness and functions throughout the pathological course of AD. With the recent expansions in the field of glial heterogeneity through innovative advances in state-of-the-art microscopy and -omics techniques, novel concepts and questions arose, notably pertaining to how the diverse microglial and astrocytic states interact with each other and with the AD hallmarks, and how their concerted efforts/actions impact the progression of the disease. In this review, we discuss the recent advances and findings on the topic of glial heterogeneity, particularly focusing on the relationships of these cells with AD hallmarks (e.g., amyloid beta plaques, neurofibrillary tangles, synaptic loss, and dystrophic neurites) in murine models of AD pathology and post-mortem brain samples of patients with AD.

Microglia as a cellular target of diclofenac therapy in Alzheimer’s disease

“…To add more complexity, studies in AD mouse models and human post-mortem tissue from AD patients showed that microglia may play distinct roles depending on disease stage and spatial distribution in the brain. 15 Microglia have ramified processes that allow them to survey their surroundings, a state called ramified or surveying micoglia. 16 Environmental triggers such as cellular debris or pathogens induce microglia activation and transformation into an ameboid state with a large, round cell body.…”

“… 18 Various other microglial states have been described, including (1) hypertrophic microglia (large cell bodies with short and thick processes) in aged patients with AD with Braak stage IV-VI, (2) dystrophic or senescent microglia (with spherical swellings in their processes, lipofuscin deposits, and positive staining for L-ferritin) predominantly near tau pathology in AD human brain, and (3) dark microglia (with ramified dark processes due to accumulation of markers indicating oxidative stress, e.g., dilated endoplasmic reticulum and altered mitochondria) near axon terminals and dendritic spines in brains of 14-month-old APP/PS1 mice (AD mouse model expressing chimeric human/mouse APP and mutant PSEN1). 15 In addition to the phenotypic heterogeneity, microglia in AD are characterized by a vast heterogeneity of genetic signatures and cytokine expression profiles. Genome-wide association studies identified triggered receptor expressed on myeloid cells ( Trem2 ) as a crucial driver of microglial activation and appearance of disease-associated microglia (DAM) in AD.…”

“… 26 Additional microglial states in AD mouse models include lipid droplet accumulating microglia (LDAM), microglial amyloid beta response proteins (MARP), and neurodegenerative disease phenotype (MGnD) microglia. 15 The presence of the DAM signature and other microglial signatures in human brain remains controversial. Gerrits et al 27 described enrichment of DAM genes (e.g, Lpl, Itgax ) in tissues derived from AD patients compared to healthy controls.…”

“… 30 Astrocytes are characterized by star-like branches that have the ability to ramify further in response to micro-environmental changes. 15 In humans, reactive astrogliosis around SPs is found in early and moderate stages of AD, whereas astrocytic atrophy and paralysis is associated with late stages of disease. 31 On a molecular level, astrocytes are heterogenous and undergo multiple distinct transcriptional states.…”

Editorial: Cannabinoids in neuroinflammation, neurodegeneration and pain: Focus on non-neuronal cells

“…Alterations of the cannabinoid system are associated with the inflammatory processes of these conditions, but intriguingly, are also implicated in the alterations in affect which may co-occur (Vecchiarelli et al, 2021). Non-neuronal cells in the central nervous system are in particular related to the pathogenesis, maintenance and/or alleviation of neuroinflammatory, neurodegenerative and pain states (Kelly et al, 2020;Šimončičová et al, 2022;St-Pierre et al, 2022). To further elucidate the role of cannabinoids in these disease contexts, this Research Topic includes a collection of primary research articles and a mini review on the role of cannabinoids in these states in particular in non-neuronal cells.Two primary research articles in the collection investigate the role of enzymes that metabolize N-acylethanolamines, including the primary endocannabinoid, Narachidonoylethanolamine (anandamide or AEA).…”