A Novel Mouse Model of Alzheimer’s Disease Exhibits Pathology through Synergistic Interactions of Amyloid-b, Tau, and Reactive Astrogliosis

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive impairment and progressive neurodegeneration. The pathological hallmarks of AD are amyloid-β plaques, neurofibrillary tangles, and reactive astrogliosis in the brain. To develop preventive diagnostic, and therapeutic strategies for AD, establishing animal models that recapitulate the pathophysiological process of AD is essential. While current transgenic mouse models offer insights into AD pathology, they often fail to replicate human AD complexity. Additionally, understanding the interplay between plaques, tangles, and reactive astrogliosis is challenging with traditional transgenic mouse models lacking spatial and temporal-specific genetic manipulation. We introduce a novel AD mouse model, APP/PS1-TauP301L-Adeno mice, to rapidly induce pathological symptoms and further understand AD pathology. We induce neurofibrillary tangles and severe reactive astrogliosis by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampus of 5-month-old APP/PS1 mice. Three months post-injection, these mice exhibit pronounced astrogliosis, significant accumulation of amyloid-β plaque and neurofibrillary tangles, accelerated neuronal loss, elevated astrocytic GABA levels, and spatial memory deficits. These AD pathological features are less prominent in AAV-TauP301L-expressing APP/PS1 mice without additionally augmented reactive astrogliosis. These findings suggest that the induction of severe reactive astrogliosis exacerbates several AD pathological features in conditions involving accumulation of amyloid-β plaque and neurofibrillary tangles. Our novel AD mouse model provides a valuable tool for advancing potential therapeutic research for AD.