The influence of mutant genes APP and PSEN1 on hippocampal asymmetry in 5xFAD mice, transgenic model of Alzheimer disease

Alzheimer’s disease (AD) is an age-related neurodegenerative pathology and one of the primary causes of dementia associated with memory and cognitive impairment. The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory encoding, and it undergoes significant changes in AD. To study the underlying mechanisms of AD and to test new therapeutic agents, mouse models of this pathology are developed. One of the most popular and relevant models for AD research is the 5xFAD transgenic mouse strain carrying mutant human genes, specifically: amyloid beta precursor protein (APP) and presenilin-1 (PSEN1). The aim of this study was to investigate the influence of mutant APP and PSEN1 transgenes on the microstructure of the hippocampal DG in six-month-old heterozygous male 5xFAD transgenic mice using diffusion tensor magnetic resonance imaging (DTI-MRI) combined with immunohistochemical analysis. A special emphasis was placed on assessing hippocampal asymmetry, which had not been previously investigated in 5xFAD mice. In the hippocampal DG of both hemispheres in male 5xFAD mice, an elevated level of betaamyloid was detected compared to the wild-type control group, combined with a higher density of microglia, but no differences were found in the level of neurogenesis. Along with this, hippocampal asymmetry was discovered in male 5xFAD mice, manifesting as an increased volume of the right hippocampus, a decreased level of fractional anisotropy in the right hippocampal DG, and a reduced neuron density in the left DG compared to the wild-type. Based on our results, it can be concluded that mutant human APP and PSEN1 genes cause alterations in the hippocampal DG, which may open new possibilities for the early diagnosis of Alzheimer’s disease. The identified changes in hippocampal volume and its asymmetry could become important biomarkers characterizing this pathology.

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