Novel mouse model of Alzheimer's disease exhibits pathology through synergistic interactions among amyloid-β, tau, and reactive astrogliosis

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 AAV _DJ-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 AAV-TauP301L-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.