Astrocyte‐Specific Phenotyping of <scp>FAD^4T</scp> as an Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, characterized by memory decline and behavioral changes. Its pathological features include senile plaques, neurofibrillary tangles, and reactive gliosis, comprising abnormal accumulations of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein surrounded by reactive astrocytes and microglia. Recently, it has emerged that severe reactive astrocytes and MAOB-dependent production of GABA and H₂O₂ are the real causes of learning and memory impairment and neurodegeneration. Diverse mouse models for AD have been developed to clarify pathological mechanisms and discover therapeutic strategies and drugs. However, there are many shortfalls and discrepancies among them. A new AD mouse model named FAD^4T has been developed to overcome various shortcomings. Here, we employed astrocyte-focused screening procedures to examine the pathological features of FAD^4T as an AD model. Our results revealed that the FAD^4T mice showed abnormal accumulation of Aβ plaques in overall brain regions at 6 and 12 months. We found astrocytic hypertrophy with a significant elevation of GFAP and LCN2. However, the expressions of MAOB and iNOS, a severe reactive astrocyte marker, were unchanged. Electrophysiological and behavioral analysis indicated aberrant tonic GABA release, reduced neuronal activity, and impaired CA1-specific memory. These findings demonstrate that FAD^4T mice mimic pathological and functional features of AD, different from other AD mouse models. These findings demonstrate that FAD^4T mimics some features of AD patients but lacks other important features, such as severe reactive astrocytes and neurodegeneration. This astrocyte-focused screening method offers valuable tools for advancing AD research and developing new therapeutic strategies.