Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes

Abstract

AbstractBackgroundStudies in animal models of Alzheimer’s disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction, but whether and how AD‐related neurophysiological alterations translate between mice and men remains uncertain.MethodWe characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early changes. Longitudinal local field potential recordings were peformed in 3‐12‐month‐old APP/PS1 mice and cross‐sectional magnetoencephalography recordings in pre‐symptomatic human APP and PSEN1 mutation carriers. Recordings were acquired of the left hippocampus, frontal and parietal cortex. We performed spectral activity and functional connectivity analyses and results were compared with wildtype control mice and healthy age‐matched human subjects.ResultAPP/PS1 mice showed increased aboslute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 months of age. Relative power showed an overall shift from lower to higher fequencies over almost the entire recording period and across all three brain regions. There was a trend for reduced peak frequency in APP/PS1 mice at 3‐4 months of age. Human mutation carriers did not show changes in power except for an increase in relative theta power in the hippocampus. Parietal cortex and hippocampal peak frequency were reduced in human mutation carriers. In both models, significant alteration in functional connectivity were detected in theta, alpha, beta and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers (Table 1).ConclusionIn conclusion, both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one‐to‐one between species. Alterations in spectral characteristics and functional connectivity in mice should be interpreted with care and may be due to overexpression of amyloid in combination with absence of tau pathology in cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models provide better translation to the human AD continuum.