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1.
bioRxiv ; 2024 Apr 14.
Article in English | MEDLINE | ID: mdl-38645230

ABSTRACT

The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. Permeability of the BBB to lipophilic molecules shows circadian variation due to rhythmic transporter expression, while basal permeability to polar molecules is non-rhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated lipopolysaccharide (LPS) injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions, then examined BBB permeability to a polar molecule, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in paracellular leak across the BBB specifically following evening LPS injection. Evening LPS led to persisting glia activation and inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion or through keeping mice in constant darkness. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown and reveals time-of-day as a key regulator of inflammatory BBB disruption.

3.
Trends Mol Med ; 29(12): 974-975, 2023 12.
Article in English | MEDLINE | ID: mdl-37872024

ABSTRACT

Time-restricted feeding (TRF) has emerged as a means of synchronizing circadian rhythms, which are commonly disrupted in Alzheimer's disease (AD). Whittaker et al. demonstrate that TRF exerts protective effects in two mouse models of AD. We discuss the effects of TRF on brain health and mechanisms linking TRF to neurodegeneration.


Subject(s)
Alzheimer Disease , Mice , Animals , Humans , Alzheimer Disease/etiology , Circadian Rhythm , Disease Models, Animal , Intermittent Fasting
4.
Nat Commun ; 14(1): 5197, 2023 08 25.
Article in English | MEDLINE | ID: mdl-37626048

ABSTRACT

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.


Subject(s)
Neurodegenerative Diseases , Tauopathies , Animals , Male , Mice , Disease Models, Animal , Inflammation/genetics , Lipid Droplets , Microglia , Tauopathies/genetics
5.
Neuron ; 111(15): 2383-2398.e7, 2023 08 02.
Article in English | MEDLINE | ID: mdl-37315555

ABSTRACT

The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.


Subject(s)
Synucleinopathies , Tauopathies , Animals , Humans , Mice , Adaptor Proteins, Signal Transducing/metabolism , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Amyloid beta-Peptides/metabolism , Apoptosis Regulatory Proteins/metabolism , ARNTL Transcription Factors/genetics , Astrocytes/metabolism , Synucleinopathies/metabolism , tau Proteins/genetics , tau Proteins/metabolism , Tauopathies/metabolism
6.
Proc Natl Acad Sci U S A ; 120(20): e2220551120, 2023 05 16.
Article in English | MEDLINE | ID: mdl-37155839

ABSTRACT

An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion of Bmal1 influences endolysosome function, autophagy, and protein degradation dynamics. In vitro, Bmal1-deficient astrocytes exhibit increased endocytosis, lysosome-dependent protein cleavage, and accumulation of LAMP1- and RAB7-positive organelles. In vivo, astrocyte-specific Bmal1 knockout (aKO) brains show accumulation of autophagosome-like structures within astrocytes by electron microscopy. Transcriptional analysis of isolated astrocytes from young and aged Bmal1 aKO mice indicates broad dysregulation of pathways involved in lysosome function which occur independently of TFEB activation. Since a clear link has been established between neurodegeneration and endolysosome dysfunction over the course of aging, this work implicates BMAL1 as a key regulator of these crucial astrocyte functions in health and disease.


Subject(s)
Circadian Clocks , Animals , Mice , ARNTL Transcription Factors/metabolism , Astrocytes/metabolism , Autophagy , Circadian Clocks/genetics , Circadian Rhythm/physiology , CLOCK Proteins/genetics , CLOCK Proteins/metabolism , Lysosomes/metabolism
7.
Sci Transl Med ; 12(574)2020 12 16.
Article in English | MEDLINE | ID: mdl-33328329

ABSTRACT

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1 knockdown increased phagocytosis of zymosan particles and of ß-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory Chi3l1 induction.


Subject(s)
Alzheimer Disease , Circadian Clocks , Alzheimer Disease/genetics , Amyloid beta-Peptides , Animals , Astrocytes , Chitinase-3-Like Protein 1/genetics , Circadian Clocks/genetics , Humans , Mice , Mice, Transgenic
8.
Virology ; 529: 186-194, 2019 03.
Article in English | MEDLINE | ID: mdl-30716580

ABSTRACT

Human Cytomegalovirus (HCMV) is an opportunistic pathogen that causes substantial disease in neonates and immunocompromised individuals. Reverse genetic analysis of the HCMV genome is a powerful tool to dissect the roles that various viral genes play during infection. However, genetic engineering of HCMV is hampered by both the large size of the HCMV genome and HCMV's slow replication cycle. Currently, most laboratories that genetically engineer HCMV employ Bacterial Artificial Chromosome (BAC) mediated recombineering, which is a relatively lengthy process. We explored an alternative method of producing recombinant HCMV using the CRISPR/Cas9 system. We employed both homologous recombination (HR) and Non-homologous end-joining (NHEJ)-based methods, and find that each approach is capable of efficiently mutating the HCMV genome, with optimal efficiencies of 42% and 81% respectively. Our results suggest that CRISPR-mediated genomic engineering of HCMV is competitive with BAC-mediated recombineering and provide a framework for using CRISPR/Cas9 for mutational analysis of the HCMV genome.


Subject(s)
CRISPR-Cas Systems , Cytomegalovirus/genetics , Genetic Engineering/methods , Genome, Viral/genetics , Humans
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