Astrocytes in selective vulnerability to neurodegenerative disease

Abstract

Selective vulnerability of specific brain regions and cell populations is a hallmark of neurodegenerative disorders. Mechanisms of selective vulnerability involve neuronal heterogeneity, functional specializations, and differential sensitivities to stressors and pathogenic factors. In this review we discuss the growing body of literature suggesting that, like neurons, astrocytes are heterogeneous and specialized, respond to and integrate diverse inputs, and induce selective effects on brain function. In disease, astrocytes undergo specific, context-dependent changes that promote different pathogenic trajectories and functional outcomes. We propose that astrocytes contribute to selective vulnerability through maladaptive transitions to context-divergent phenotypes that impair specific brain regions and functions. Further studies on the multifaceted roles of astrocytes in disease may provide new therapeutic approaches to enhance resilience against neurodegenerative disorders.

Keywords: dementia; glia; heterogeneity; neuropathology; proteinopathy; resilience.

Figure 1.. Vulnerability to neurodegenerative disorders is multifactorial.

Multiple intrinsic variables affect the onset and progression of neurodegenerative disease, including age and genetics but also environmental and lifestyle factors. These and other variables influence the complex multicellular interactions between different cell types in the brain and their functions. Dynamic molecular changes, detrimental and protective, occur within multiple cell types and affect cell-cell interactions, contributing to disease complexity. Together, these changes result in nonlinear pathogenesis and selective vulnerability within specific subpopulations of cells, brain regions, and individuals. Figure created using BioRender.com.

Figure 2.. Molecular, structural, and functional diversity in astrocytes.

Astrocyte diversity involves cell-autonomous molecular features, structural and positional identity of astrocytes throughout the brain, and the integration of astrocyte populations into their functional contexts. All three aspects of heterogeneity are interconnected, and facilitate precise, dynamic, and multifaceted responses by astrocytes to various physiological and pathological signals. Ultimately, astrocytic responses have direct and indirect effects on neuronal function and survival and thereby have major roles in the pathogenesis of neurodegenerative diseases. Abbreviations: ATP, adenosine triphosphate; ROS, reactive oxygen species. Figure created using BioRender.com.

Figure 3.. Astrocytes may contribute to selective vulnerability in disease through divergent, context-dependent phenotypes that affect specific brain regions and functions.

(a) Aberrant proteins implicated in disease are cleared from the brain through various mechanisms, including AQP4-dependent protein removal. Astrocytes in basal brain regions may have a higher clearance burden and, in conjunction with changes in AQP4 localization and expression, might promote selective vulnerability in the basal regions. (b) Cortical astrocytes contact more blood vessels and fewer synapses per cell as compared to hippocampal astrocytes. The resulting higher metabolic load carried by hippocampal astrocytes may predispose hippocampal synapses and other neural elements to metabolic vulnerability and the detrimental effects of neural hyperexcitability. (c) Astrocytes regulate neurotransmission in a state-dependent and region-specific manner. In FTD, thalamic astrocytes may remove less glutamate via surface transporters and promote synaptic loss and, in brain injury, remove less GABA and induce hyperexcitability. Aberrant TDP-43 accumulation in hippocampal astrocytes promotes region-specific expression of chemokines that induce presynaptic changes and aberrant excitatory transmission. Hippocampal astrocytes in AD overproduce GABA and impair neuronal function through increases in tonic inhibition. (d) Astrocytes can differentially modulate synaptic formation and loss. Striatal astrocytes in the context of HD-related pathology have altered G_i/o-coupled signaling leading to gene expression changes that impair synaptogenesis. In aging, subpopulations of hippocampal astrocytes have disrupted proteosomes and lysosomes, which impairs synaptic pruning and secretion of synaptogenic factors. Abbreviations: α-syn, alpha-synuclein; Aβ, amyloid-beta; AD, Alzheimer’s disease; AQP4, aquaporin-4; FTD, frontotemporal dementia; GABA, γ-aminobutyric acid; G_i/o, G_i/o-coupled receptor signaling; GPCRs, G protein-coupled receptors; TDP-43, transactive response DNA-binding protein of 43 kDa. Figure created using BioRender.com.

Figure 4.. Astrocytes promote context-dependent effects in health and disease.

(a) Astrocytes are sensitive to various cues in their microenvironment and have diverse molecular, structural, and functional states as a result of the specific combination of cues received by individual astrocytes. These combinatorial inputs instruct astrocytes to assume various context-integrated states that enable normal brain function. (b) In disease and other conditions, aberrant inputs and perturbations affect individual astrocytes differently and may shift subsets or subcompartments of astrocytes into context-divergent states that selectively enhance or disrupt specific aspects of brain function. Figure created using BioRender.com.