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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features, including amyloid-β plaques, neurofibrillary tangles, and reactive astrogliosis. Developing effective diagnostic, preventative, and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease. Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD. Additionally, these models are limited in their ability to elucidate the interplay among amyloid-β plaques, neurofibrillary tangles, and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation. In this study, we introduce a novel AD mouse model (APP/PS1-TauP301L-Adeno mice) designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms. Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice. Three months post-injection, these mice exhibited pronounced astrogliosis, substantial amyloid-β plaque accumulation, extensive neurofibrillary tangles, accelerated neuronal loss, elevated astrocytic GABA levels, and significant spatial memory deficits. Notably, these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis. These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-β plaque and neurofibrillary tangle-associated pathology. The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD. [ABSTRACT FROM AUTHOR]

Metabolic impairments and liver and adipose depots alterations were reported in subjects with Alzheimer's disease (AD), highlighting the role of the liver–adipose–tissue–brain axis in AD pathophysiology. The gut microbiota might play a modulating role. We investigated the alterations to the liver and white/brown adipose tissues (W/BAT) and their relationships with serum and gut metabolites and gut bacteria in a 3xTg mouse model during AD onset (adulthood) and progression (aging) and the impact of high-fat diet (HFD) and intranasal insulin (INI). Glucose metabolism (18FDG-PET), tissue radiodensity (CT), liver and W/BAT histology, BAT-thermogenic markers were analyzed. 16S-RNA sequencing and mass-spectrometry were performed in adult (8 months) and aged (14 months) 3xTg-AD mice with a high-fat or control diet. Generalized and HFD resistant deficiency of lipid accumulation in both liver and W/BAT, hypermetabolism in WAT (adulthood) and BAT (aging), abnormal cytokine–hormone profiles, and liver inflammation were observed in 3xTg mice; INI could antagonize all these alterations. Specific gut microbiota–metabolome profiles correlated with a significant disruption of the gut–microbiota–liver–adipose axis in AD mice. In conclusion, fat dystrophy in liver and adipose depots contributes to AD progression, and associates with altered profiles of the gut microbiota, which candidates as an appealing early target for preventive intervention. [ABSTRACT FROM AUTHOR]