Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

Brandebura, Ashley N.; Paumier, Adrien; Onur, Tarik Seref; Allen, Nicola J.

doi:10.1038/s41583-022-00641-1

Cited by 217 publications

(116 citation statements)

References 201 publications

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“…The KEGG pathway analysis of astrocytes showed that this cluster is involved in Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, retrograde nerve signaling, GABAergic synapses, and lysosomal pathways ( Figure 5E ), indicating that astrocyte reactivity is associated with neurological disorders. Moreover, the expression of reactivity marker genes of astrocytes, such as Id3 , Npc2 and Prdx6 28 , Alzheimer’s disease risk-related genes Ctsb , Ctsd , Ctsl , S100a6 , Itgab5 and Vsir 29 and interferon stimulated genes Gbp3 , Gbp2 , Irgm1 , Iigp1 , Igtp , Cxcl10 were all up-regulated in the astrocyte of brain 30–32 ( Figure 5F, Figure S9B ). All these data suggest that the bacteria are involved in alternations of brain homeostasis, by switching both microglia and astrocytes from quiescence to activation though bacterial infection-related pathways.…”

Section: Resultsmentioning

confidence: 99%

Neurological Disorder after Severe Pneumonia is Associated with Translocation of Bacteria from Lung to Brain

Yao

Wang

et al. 2022

Preprint

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Neurological disorders after severe acute pneumonia have been attacked much attention in recent years. However, the underline mechanisms remain not very clear. Here we show that these neurological syndromes after severe acute pneumonia are partly attributed to the translocation of bacteria from the lung to the brain during acute pneumonia. We detected an emerging and increased bacteria in the brain tissue of mice with lipopolysaccharide-induced experimental severe pneumonia. Interestingly, using 16S rDNA amplification sequencing, similarities were found between the brain's flora species and those of the lungs, indicating the bacteria in the brain may come from the lung. We also observed the impairment of the lung-blood barrier and brain-blood barrier, simultaneously, allowing lung bacteria invade the brain during pneumonia. An elevated microglia and astrocytes activation markers signature though bacterial infection-related pathways are observed by single-cell RNA sequencing, indicating a bacteria-induced disruption of brain homeostasis. Rapamycin delivered by platelet-derived extracellular vesicles provides an effective strategy to rescue the brain microenvironment and neurological disorders. Collectively, we identify lung bacteria that play a role in altering brain homeostasis, which provides new insight into the mechanism of neurological syndromes after severe pneumonia.

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Section: Resultsmentioning

confidence: 99%

Neurological Disorder after Severe Pneumonia is Associated with Translocation of Bacteria from Lung to Brain

Yao

Wang

et al. 2022

Preprint

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“…These discoveries have clinical implications as they suggest that pathological processes involving any of these cell types can eventually result in loss of harmony among these cells and manifest as cognitive impairments. Indeed, accumulating evidence suggests the crucial contributions of non-neuronal cells in the pathology of diverse neurodegenerative disorders including Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis (Brandebura et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Astrocytic L-lactate signaling in the anterior cingulate cortex is essential for schema memory and neuronal mitochondrial biogenesis

Akter

Hasan

Ramkrishnan

et al. 2023

Preprint

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Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic Gi signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and schema memory is not clear. Here, using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic Gi pathway activation in ACC causes significant impairment in flavor-place paired associates (PA) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments were mediated by decreased L-lactate in ACC due to astrocytic Gi activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation was associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in ACC upon Gi activation. Our study also reveals that L-lactate mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 and NMDA receptor activity – discovering a previously unrecognized signaling role of L-lactate. These findings expand our understanding of the role of astrocytes and L-lactate in brain functions.

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“…One such example, in a mouse model of Alzheimer's disease, reveals that astrocyte Ca 2+ hyperactivity precedes and induces synaptic impairments in nearby neurons 66,67 . These ideas are forcing a change in perception of how brain disorders develop and progress moving away from a neuro-centric cascade, placing glial cells in the spotlight [68][69][70][71][72][73] .…”

Section: Discussionmentioning

confidence: 99%

Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation

Adedipe

Depaauw-Holt

Latraverse-Arquilla

et al. 2022

Preprint

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Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioural and cognitive deficits. While the effects of early-life stress (ELS) on neuronal function have been well-described, we still know very little about the contribution of non-neuronal brain cells to the cellular and behavioural adaptations following ELS. Here, using a rodent model of ELS, we report that astrocytes play a key role in mediating the impact of stress on amygdala-dependent behaviour and synaptic plasticity during adolescence. We report that ELS induces generalisation of fear, associated with increased levels of circulating corticosterone and activation of glucocorticoid receptors in astrocytes. In addition, we identify astrocyte glucocorticoid receptors as targets, mediating ELS-induced cognitive and synaptic impairments. This work establishes astrocytes as key elements in amygdala-dependent memory, and as central mediators of the effects of stress on cognitive function via stress hormone signalling pathways.

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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

Cited by 217 publications

References 201 publications

Neurological Disorder after Severe Pneumonia is Associated with Translocation of Bacteria from Lung to Brain

Neurological Disorder after Severe Pneumonia is Associated with Translocation of Bacteria from Lung to Brain

Astrocytic L-lactate signaling in the anterior cingulate cortex is essential for schema memory and neuronal mitochondrial biogenesis

Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation

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