Phenotypes of Astrocytes in Alzheimer's Disease

Astrocytes are involved in various processes in the central nervous system (CNS) and are the most abundant cell type in the CNS. Alzheimer's disease (AD) is a neurodegenerative disorder with symptoms of cognitive and behavioral deficits. Astrocytes are involved in various neurodegenerative diseases such as AD during the transformation process.

Recent studies have found that astrocytes associated with AD may exhibit various phenotypes during AD, such as morphological and functional dysregulation of astrocytes associated with neuronal cell death in AD, and that the study of astrocyte subtypes associated with AD can help identify novel pathophysiological mechanisms in AD.

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Creative Biolabs, a leading provider of comprehensive, high-quality research tools and service support for neuroscience research, provides the following related services to explore phenotypes of astrocytes in AD.

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Reactive Phenotypes of Astrocytes in AD

Astrocytes can be transformed into reactive astrocytes through morphological, molecular, and functional changes under different pathological conditions, and reactive astrocytes induce neuropathology and neurodegeneration in neurodegenerative diseases and toxic neurological environments. As part of astrocyte polarization, reactive astrocytes can be converted to pro-inflammatory factors, the neurotoxic A1 phenotype (A1 astrocytes) or anti-inflammatory factors, the neuroprotective A2 phenotype (A2 astrocytes).

• A1 astrocytes show up-regulation of expression in the gene expression of the classical complement cascade associated with synaptic disruption, including glial fiber acidic protein (GFAP), S100 calcium-binding protein B (S100B), and complement C3 (C3).
• A2 Astrocytes show up-regulation of expression in the gene expression of a number of neurotrophic factors that promote neuronal survival and growth. These include cytokine factor 1 (Clcf1), transglutaminase 1 (Tgm1), pentraxin 3 (Ptx3), etc.

Death Phenotypes of Astrocytes in AD

Apoptosis is involved in various diseases of the nervous system, and the presence of large numbers of apoptotic cells in the brains of AD patients is a pathological feature. Apoptosis of astrocytes may contribute to the study of AD pathogenesis.

• The number of TUNEL-positive apoptotic astrocytes was increased in the brains of AD patients. The density of TUNEL-positive astrocytes is correlated with the density of nucleated and nucleated senile plaques, which are polymorphic Aβ-protein deposits. TUNEL-positive apoptotic astrocytes in the brains of AD patients showed fragmentation and cytoplasmic vesicular regression changes.
• Ferroptotic astrocytes have been identified in AD. The number of ferroptotic astrocytes is increased in the brains of AD patients, and markers of oxidative stress associated with ferroptosis, including 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) are elevated in astrocytes from the cerebral cortex of AD patients. Expression of genes associated with ferroptosis such as iron-responsive element-binding protein 2 (Ireb2), citrate synthase (Cs), ribosomal protein L8 (Rpl8), and prostaglandin-endoperoxide synthase 2 (Ptgs2) was upregulated.

Senescence Phenotypes of Astrocytes in AD

Senescence is a major risk factor for the pathogenesis of AD, and cellular senescence is a hallmark of aging. Cellular senescence in the brain may link the process of cellular senescence to the degree of AD pathogenesis. The senescence of astrocytes has been linked to the pathogenesis of AD.

• The number of senescent astrocytes is increased in patients with AD. H2AX, as part of the nucleosome structure, is increased in the hippocampus and cerebral cortex of patients with AD. As a marker of DNA damage in aging, γH2AX is expressed as a phosphorylated form of H2A in response to the formation of double-strand breaks in chromosomal DNA.
• Senescence-related genes such as Cdkn2a show increased expression in astrocytes.

Dysfunctional Phenotypes of Astrocytes in AD

Astrocytes play an important role in maintaining homeostasis of neural circuits and regulating neuronal activity through intracellular calcium signaling. In early AD symptoms, dysfunction in astrocyte calcium signaling can lead to over-excitation of neural networks in AD patients. Dysregulation of calcium signaling in astrocytes may help to study the pathological progression of AD.

• In studies of astrocyte calcium signaling in AD patients, the expression of inositol 1,4,5-trisphosphate receptor type 2 (ITPR20), a channel for intracellular calcium release, was reduced in astrocytes from the brains of AD patients.
• In studies of calcium signaling in mouse AD astrocytes, reduced calcium signaling was addressed by decreasing Itpr2 expression in astrocytes prior to Aβ plaque accumulation during the early stages of AD in AppNL-F model mice.

Fig. 1 The pathological phenotypes of astrocytes include the reactive phenotype, the death phenotype, the senescence phenotype and functional impairment phenotypes in AD.¹

We describe astrocyte phenotypes in AD, including reactive phenotypes, death phenotypes, senescence phenotypes, and dysfunction phenotypes. The exploration of astrocyte phenotypes may have implications for the study of AD pathogenesis.

In collaboration with Creative Biolabs, we continue to push the research on therapies for AD that control the pathology of astrocytes in addition to research targeting the pathology of the targets Aβ and tau.

Reference

1. Kim, Junhyung, et al. "Pathological phenotypes of astrocytes in Alzheimer's disease." Experimental & Molecular Medicine (2024): 1-5.

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