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Brain Commun. 2024 Jun 25;6(4):fcae218. doi: 10.1093/braincomms/fcae218. eCollection 2024.
ABSTRACT
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 App NL-G-F triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (App hu mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-β proteins, microglial and astrocytic activation and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-β oligomers were abundant in the brains of App hu mice in the absence of classical amyloid-β plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. In contrast, both high levels of amyloid-β oligomers and numerous plaques accumulated in App NL-G-F mice in association with substantial astrocytic and microglial activation. The increase in amyloid-β oligomers over time was more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-β oligomers than with amyloid-β plaques in App NL-G-F mice, which also showed age-dependent decreases in neuronal and synaptic density markers. A comparative study of the two models highlighted the dependence of glial and neuronal pathology on the nature and aggregation state of the amyloid-β peptide. Astrocyte activation and neuronal pathology appeared to be more strongly associated with amyloid-β oligomers than with amyloid-β plaques, although amyloid-β plaques were associated with microglia activation.
PMID:39035420 | PMC:PMC11258573 | DOI:10.1093/braincomms/fcae218
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Associations of amyloid-beta oligomers and plaques with neuropathology in the App (NL-G-F) mouse
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