Publications by authors named "Robert C J Muirhead"
Amyloid-β pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer's disease. In this study, we investigated the relationships between the levels of amyloid-β oligomers, amyloid-β plaques, glial activation and markers related to neurodegeneration in the triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein ( mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry.
View Article and Find Full Text PDFAging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 (up to twofold) with AD relative to NDC.
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- Brain perfusion and blood-brain barrier integrity are compromised early in Alzheimer's disease, leading to increased vascular issues.
- Single nucleus RNA sequencing revealed that endothelial cells in Alzheimer's patients show gene expressions linked to AD susceptibility, particularly involving β-amyloid and impairments in vascular signaling.
- The study suggests that targeting vascular inflammation and enhancing angiogenesis may help reduce vascular dysfunction and potentially slow down the onset or progression of Alzheimer's disease.
Article Synopsis
- Microglial activation is crucial in diseases that involve neuroinflammation and neurodegeneration, with PET scans using TSPO to detect inflammation in the brain, although interpreting these results can be tricky.* -
- The study finds that while TSPO expression increases in activated microglia in mouse models, it doesn't change in human diseases, indicating a difference in how TSPO is regulated across species.* -
- Genetic differences in TSPO expression linked to the transcription factor AP1 are noted, suggesting that human TSPO-PET signals are more about the presence of inflammatory cells rather than their activation state.*
To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type.
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