An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology

Sheehan, Patrick W.; Nadarajah, Collin J.; Kanan, Michael F.; Patterson, Jessica N.; Novotny, Brenna C; Lawrence, Jennifer H.; King, Melvin W.; Brase, Logan; Inman, Casey E.; Yuede, Carla M.; Patel, Tirth K.; Harari, Oscar; Benítez, Bruno A.; Davis, Albert A.; Musiek, Erik S.

doi:10.1016/j.neuron.2023.05.006

Cited by 34 publications

(20 citation statements)

References 60 publications

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“…88 In mouse models of tau and alpha-synuclein proteinopathy, astrocyte-specific Bmal1 deletion can increase macroautophagy and mitigate toxic protein aggregation (Figure 2). 83 Although it is important to consider that BMAL1 can mediate noncircadian functions, it remains unclear which effects of Bmal1 deletion in astrocytes are due to abrogated cellular circadian rhythms, as opposed to nonrhythmic phenomena. However, these data show that disrupting the core molecular clock in astrocytes via Bmal1 deletion can have striking effects on astrocyte gene expression, morphology, and activation state and can strongly influence brain pathology.…”

Section: Glial Clocks Astrocytesmentioning

confidence: 99%

“…Bmal1 deletion in astrocytes leads to astrogliosis, with increased reactivity, autophagy/lysosomal degradation, and phagocytosis. 82,83 Rev-erbα-deficient microglia have a more variable response. There is increased reactivity, lipid droplet formation, and synaptic/Aβ phagocytosis; however, there is less extracellular Tau phagocytosis.…”

Section: Oligodendrocytesmentioning

confidence: 99%

Section: Glial Clocksmentioning

confidence: 99%

“…Microglial-specific Rev-erbα deletion induces astrogliosis in the hippocampus, while astrocyte-specific Bmal1 deletion does not significantly increase disease-associated microglia markers. 83,85 formation, migration, and differentiation-is dependent on neural derived-factors. Immediately following CNS injuries, such as ischemic stroke, there is widespread oligodendrocyte cell death and loss of this critical neuraloligodendrocyte support.…”

Section: Oligodendrocytesmentioning

confidence: 99%

“…**There is some glial cell crosstalk using cell-specific gene deletion models; however, this seems to be highly cell dependent. Microglial-specific Rev-erbα deletion induces astrogliosis in the hippocampus, while astrocyte-specific Bmal1 deletion does not significantly increase disease-associated microglia markers 83,85. VIP indicates vasoactive intestinal peptide; and ZT, zeitgeber time.…”

mentioning

confidence: 99%

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Circadian Biology and the Neurovascular Unit

Li,

Tiedt,

Lawrence

et al. 2024

Circulation Research

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Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke.

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Section: Glial Clocks Astrocytesmentioning

confidence: 99%

Section: Oligodendrocytesmentioning

confidence: 99%

Section: Glial Clocksmentioning

confidence: 99%

Section: Oligodendrocytesmentioning

confidence: 99%

mentioning

confidence: 99%

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Circadian Biology and the Neurovascular Unit

Li,

Tiedt,

Lawrence

et al. 2024

Circulation Research

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Astrocyte–Neuron Interactions in Alzheimer’s Disease

Muñoz-Castro,

Serrano-Pozo

2024

Advances in Neurobiology

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Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway

Sweeney,

Kim,

Morrison

et al. 2024

Acta Neuropathol

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Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer’s disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.

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An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology

Cited by 34 publications

References 60 publications

Circadian Biology and the Neurovascular Unit

Circadian Biology and the Neurovascular Unit

Astrocyte–Neuron Interactions in Alzheimer’s Disease

Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway

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