Brain Atrophy and Neuron Loss in the 5xFAD Mouse Model of Alzheimer's Disease

Abstract

The 5xFAD mouse model is a well-known genetic model of Alzheimer’s disease (AD) that replicates key markers of the disease in humans and is widely used in AD research. However, clear and comprehensive evidence of neurodegeneration in this model is lacking. In this study, serial stereological cryosections from female 5xFAD transgenic and wild-type littermate mice at 9 and 14 months of age were analysed using machine learning-based tools, and the structural and cellular changes were compared between genotypes. We revealed a significant reduction in striatal and cortical volumes at 9 months, followed by hippocampal volume reduction at 14 months. At 9 months, cell detection analysis revealed a significant loss of neurons in the striatum, providing, to our knowledge, the first evidence of neuronal loss in the striatum of 5xFAD mice. These changes precede the emergence of severe cognitive dysfunction in this model and align with imaging data from human AD patients showing that striatal neurodegeneration correlates with the appearance of dementia. Although the striatum is not typically the primary focus of AD research, our findings highlight its important involvement in disease progression and as a target for further research.