Multisensory gamma stimulation promotes glymphatic clearance of amyloid
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1049874 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27139458.fastq.gz | Fastqsanger.gz | |||
| SRR27139459.fastq.gz | Fastqsanger.gz | |||
| SRR27139460.fastq.gz | Fastqsanger.gz | |||
| SRR27139461.fastq.gz | Fastqsanger.gz | |||
| SRR27139462.fastq.gz | Fastqsanger.gz |
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Project description:The glymphatic movement of fluid through the brain powerfully clears metabolic waste. We observed multisensory 40 Hz stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease, which was associated with increased aquaporin-4 polarization along astrocytic endfeet, dilated meningeal lymphatic vessels, and amyloid accumulation in cervical lymph nodes. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signaling, we found VIP+ interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms to recruit the glymphatic system to remove brain amyloid.
2023-12-23 | GSE249644 | GEO
Project description:NOTCH3 mutation results in development of cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), the most common monogenic small vessel disease. Up to date, specific treatment against CADASIL is scarce. Here, we report that both glymphatic influx and efflux are impaired in CADASIL mouse models (Notch3R170C), which impedes waste clearance and promotes brain senescence. In accordance, brain atrophy in CADASIL patients is associated with perivascular space enlargement, indicating that glymphatic impairment contributes to advanced brain senescence in CADASIL. The glymphatic malfunction in CADASIL is attributed to diminished AQP4 expression in astrocytic endfeet, which is the core mediator of glymphatic activity. Mechanistically, AQP4 expression is regulated by RUNX1-CMYB signaling whose activation is suppressed as a result of NOTCH3 mutation. Reinforcing AQP4 expression in astrocytes by AAV-based therapy resumes the glymphatic functions in CADASIL mice, which further prevents brain senescence. Therefore, we propose that to improve glymphatic function by reinforcing AQP4 expression is a promising therapeutic strategy in CADASIL.
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Project description:Amyloids are fibrous protein aggregates associated with age-related diseases. While these aggregates are typically described as irreversible and pathogenic, some cells utilize reversible amyloid-like structures that serve important functions. The RNA-binding protein Rim4 forms amyloid-like assemblies that are essential for translational control during S. cerevisiae meiosis. Rim4 amyloid-like assemblies are disassembled in a phosphorylation-dependent manner at meiosis II onset. By investigating Rim4 clearance, we elucidate co-factors that mediate clearance of amyloid-like assemblies in a physiological setting. We demonstrate that yeast 14-3-3 proteins bind to Rim4 assemblies and facilitate their subsequent phosphorylation and timely clearance. Furthermore, distinct 14-3-3 proteins play non-redundant roles in facilitating phosphorylation and clearance of amyloid-like Rim4. Additionally, we find that 14-3-3 proteins contribute to global protein aggregate homeostasis. Based on the role of 14-3-3 proteins in aggregate homeostasis and their interactions with disease-associated assemblies, we propose that these proteins may protect against pathological protein aggregates.
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Project description:White matter hyperintensity (WMH) is a pressing global medical issue linked to cognitive decline and stroke risk. Despite its significance, the underlying mechanisms remain unclear. Here, we directly demonstrated in humans that high WMH burden correlated with delayed glymphatic pathway drainage. Additionally, a longitudinal cohort study revealed that glymphatic dysfunction predicted WMH progression. Next, in a rat model of WMH, we confirmed the presence of impaired lymphangiogenesis and glymphatic drainage, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis and glymphatic drainage through adenoviral delivery of Vascular Endothelial Growth Factor-C (VEGF-C) mitigated microglial gliosis and white matter demyelination. Conversely, blocking the growth of meningeal lymphatics with a VEGF-C trap strategy exacerbated these changes. Our findings highlight the role of meningeal lymphatics and glymphatic pathway dysfunction in aggravating brain white matter injury and advancing WMH, providing a potential novel strategy for WMH prevention and treatment.
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Project description:Das2010 - Effect of a gamma-secretase
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This model is described in the article:
Modeling effect of a
?-secretase inhibitor on amyloid-? dynamics reveals significant
role of an amyloid clearance mechanism.
Das R, Nachbar RB, Edelstein-Keshet
L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon
AJ, Hargreaves RJ, Cook JJ.
Bull. Math. Biol. 2011 Jan; 73(1):
230-247
Abstract:
Aggregation of the small peptide amyloid beta (A?) into
oligomers and fibrils in the brain is believed to be a
precursor to Alzheimer's disease. A? is produced via multiple
proteolytic cleavages of amyloid precursor protein (APP),
mediated by the enzymes ?- and ?-secretase. In this study, we
examine the temporal dynamics of soluble (unaggregated) A? in
the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys
treated with different oral doses of a ?-secretase inhibitor. A
dose-dependent reduction of A? concentration was observed
within hours of drug ingestion, for all doses tested. A?
concentration in the CSF returned to its predrug level over the
monitoring period. In contrast, A? concentration in the plasma
exhibited an unexpected overshoot to as high as 200% of the
predrug concentration, and this overshoot persisted as late as
72 hours post-drug ingestion. To account for these
observations, we proposed and analyzed a minimal physiological
model for A? dynamics that could fit the data. Our analysis
suggests that the overshoot arises from the attenuation of an
A? clearance mechanism, possibly due to the inhibitor. Our
model predicts that the efficacy of A? clearance recovers to
its basal (pretreatment) value with a characteristic time of
>48 hours, matching the time-scale of the overshoot. These
results point to the need for a more detailed investigation of
soluble A? clearance mechanisms and their interaction with
A?-reducing drugs.
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2024-09-02 | BIOMD0000000551 | BioModels
Project description:Aging leads to a progressive deterioration in brain function, which will eventually result in cognitive decline and can develop into a dementia. The mechanisms underlying pathological cognitive decline in aging are still poorly understood. The peripheral immune system, as well as the meningeal lymphatic vasculature and the immune cells residing in the brain and meninges, are all affected by aging. Moreover, recent studies have linked the dysfunction of the meningeal lymphatic system and peripheral immunity to accelerated brain aging. We hypothesized that an age-related reduction in CCR7-dependent immune cell egress through the lymphatic vasculature mediates some aspects of aging-associated brain dysfunction, leading to cognitive decline and potentially exacerbating neurodegenerative diseases. Here, we report a reduction in CCR7 expression by meningeal T cells in aged mice and its associated increase in meningeal T-regulatory cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to cognitive impairment. Interestingly, CCR7-deficient mice also presented impaired brain glymphatic function and showed increased amyloid beta (A) deposition when crossed with the 5xFAD transgenic mouse model of Alzheimer’s disease (AD). These results show that the aging-associated decrease in CCR7 expression impacts meningeal immunity, affects different aspects of brain function and exacerbates brain A pathology, highlighting its potential as a pathogenic mechanism for cognitive decline in aging and AD.
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Project description:IFN-γ stimulation induces immunosuppression in CRC
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Project description:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.
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