Morphological and molecular alterations of reactive astrocytes without proliferation in cerebral cortex of an APP/PS1 transgenic mouse model and Alzheimer's patients

Abstract

Astrocytes are fundamental for maintaining brain homeostasis and are commonly involved in the progression of neurodegenerative diseases including Alzheimer's disease (AD). In response to injury or toxic material, astrocytes undergo activation that results in hypertrophy and process ramification. Although numerous studies have shown that reactive astrocytes are intimately related to the pathogenesis of AD, their characteristic features including morphological and molecular alterations that occur during different stages of AD progression remain to be elucidated. Here, we crossed astrocyte‐specific reporter mice hGFAP‐CreERT2;Rosa‐tdTomato with APP/PS1 mice, and then used genetic tracing to characterize the morphological profiles and expression of molecular biomarkers associated with progressive β‐amyloid deposits in the cortical region of AD mice. Expression of glutamine synthetase (GS) was lower in cortical reactive astrocytes, in contrast to the higher expression of glial fibrillary acidic protein, of APP/PS1 mice and AD patients relative to that in cortical astrocytes of wild‐type mice and age‐matched controls, respectively. GS activity was also decreased obviously in the cortex of APP/PS1 mice at 6 and 12 months of age relative to that in the wild‐type mice of the same ages. Furthermore, cortical reactive astrocytes in APP/PS1 mice and AD patients did not undergo proliferation. Finally, based on RNA‐sequencing analysis, we identified differentially expressed transcripts of signal transduction molecules involved in early induction of reactive astrocytes in the cortex of APP/PS1 mice. These findings provide a morphological and molecular basis with which to understand the function and mechanism of reactive astrocytes in the progression of AD.

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

“…The reactivity of astrocytes varies with the nature and severity of the insult or disease (Sofroniew, 2009). We recently showed that cortical reactive astrocytes in a mouse model of Alzheimer's disease and in patients with Alzheimer's disease do not undergo proliferation despite an increase in GFAP expression and hypertrophic morphology (Li, Gong, et al, 2020). By contrast, our current analysis demonstrated that early postnatal TBI of mouse cortex results in a sharp increase in the proliferation of BrdU incorporation into reactive astrocytes.…”

Astrocytes: News about Brain Health and Diseases

“…The astrocyte presentation of the disease is focused on the coordination with the other areas and in the development of new pathogenesis [ 89 , 90 ]. The relevance expected for future developments includes a general reconsideration based on the role of astrocytes, new innovative approaches to the understanding, and new therapies of diseases [ 46 , 47 , 82 , 98 ].…”

“…Highly interesting are the RNA sequences, known to identify the disease-associated astrocytes. The latter properties, present already at early levels, increase with the progression of the disease [ 82 , 89 , 98 ].…”

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

“…Other studies have shown an increased cytoskeleton hypertrophy or increased complexity of astrocytes near Aß plaques using GFAP immunolabeling in the hippocampus of 6, 12, and 18-month-old TgF344 male and female rats [Swedish mutation in APP and humanized PSEN1 (Cohen et al, 2013)] (Mampay et al, 2020), in the dentate gyrus and hippocampus CA1 of 18-month-old 3xTg male mice (Olabarria et al, 2010) and in the cerebral cortex of 3, 6 and 12-month-old APP-PS1 mice (increase in volume and process length) (Li et al, 2020). A sex-specific increase in the abundance of hypertrophic astrocytes in 7-9 month-old APP-PS1 female compared to male mice was observed in the outer molecular layer of the dentate gyrus (Richetin et al, 2017).…”