Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease

Katsouri, Loukia; Birch, Amy M.; Renziehausen, Alexander; Zach, Carolin; Aman, Yahyah; Steeds, Hannah; Bonsu, Angela; Palmer, Emily; Mirzaei, Nazanin; Ries, Miriam; Sastre, Magdalena

doi:10.1002/glia.23759

Cited by 66 publications

(59 citation statements)

References 47 publications

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“…In addition, reactive astrocytes are involved in phagocytic clearance of presynaptic dystrophies in AD (Gomez‐Arboledas et al, 2018). Ablation of reactive astrocytes in AD aggravates amyloid pathology and memory loss (Katsouri et al, 2020). By contrast, other studies have shown that reactive astrocytes play a deleterious role by regulating neuroinflammation or neurotransmitters in AD mouse models (Furman et al, 2012; Jo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Gong

et al. 2020

Glia

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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.

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Section: Discussionmentioning

confidence: 99%

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

Gong

et al. 2020

Glia

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“…IGF-I stimulates Aβ uptake by astrocytes, while inhibits it in microglia. Whereas astrocytes appear critical to determine Aβ load [68], and increased clearance of Aβ by astrocytes may result in reduced Aβ plaques [42], inhibition of Aβ uptake by microglia may also reduce plaques [69], as the role of microglial uptake of Aβ in plaque formation may be detrimental [70,71]. In accordance with a stimulatory effect of IGF-I on astrocytes, previous observations suggested that astrocyte-derived IGF-I protects neurons against Aβ toxicity through a mechanism involving its uptake [72].…”

Section: Discussionmentioning

confidence: 88%

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Herrero-Labrador

Trueba-Saiz

Martinez-Rachadell

et al. 2020

Preprint

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BackgroundObesity is a risk factor for Alzheimer´s disease (AD), but underlying mechanisms are not clear.MethodsWe analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance, and is increased in serum of overweight mice. Results Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ clearance by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced peripheral Aβ clearance and unchanged brain Aβ levels. In the brain, IGF-I favored association of its receptor (IGF-IR) with Aβ precursor protein (APP), and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association was found in overweight mice as compared to lean controls. Conclusions Collectively, these results indicate that diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ clearance probably because its brain entrance is reduced.

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“…IGF-I stimulates Aβ uptake by astrocytes, while inhibits it in microglia. Whereas astrocytes appear critical to determine Aβ load (56), and increased clearance of Aβ by astrocytes may result in reduced Aβ plaques (34), inhibition of Aβ uptake by microglia may also reduce plaques (57), as the role of microglial uptake of Aβ in plaque formation may be detrimental (58,59). In accordance with a stimulatory effect of IGF-I on astrocytes, previous observations suggested that astrocyte-derived IGF-I protects neurons against Aβ toxicity through a mechanism involving its uptake (60).…”

Section: Discussionmentioning

confidence: 88%

Diet Influences Peripheral Amyloid Β Metabolism: A Role for Circulating Insulin-Like Growth Factor I

Raquel

Trueba-Saiz

Martinez-Rachadell

et al. 2020

Preprint

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AbstractObesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on brain Aβ load, a major landmark of AD pathology. Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain Aβ clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral Aβ clearance. We found that Aβ uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral Aβ clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with Aβ precursor protein (APP), and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly less activation of brain IGF-IR phosphorylation and APP/IGF-IR association was found in overweight mice as compared to lean controls. Collectively, these results indicate that diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ clearance probably because its brain entrance is reduced.

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Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease

Cited by 66 publications

References 47 publications

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

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

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Diet Influences Peripheral Amyloid Β Metabolism: A Role for Circulating Insulin-Like Growth Factor I

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