TY - JOUR
T1 - Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes
AU - van Heusden, Fran C.
AU - van Nifterick, Anne M.
AU - Souza, Bryan C.
AU - França, Arthur S.C.
AU - Nauta, Ilse M.
AU - Stam, Cornelis J.
AU - Scheltens, Philip
AU - Smit, August B.
AU - Gouw, Alida A.
AU - van Kesteren, Ronald E.
N1 - Funding Information: This work was supported by the Netherlands Organization for Health Research and Development (ZonMW; grant #91218018 and grant #733050812). MEG scans were made possible by a research grant from Amsterdam Neuroscience. Dr. Gouw receives financial support from Vivoryon Therapeutics AG via the Amsterdam Alzheimer Center. Research of Amsterdam Alzheimer Center is part of the neurodegeneration program of Amsterdam Neuroscience. The Amsterdam Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc funds. Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/8/22
Y1 - 2023/8/22
N2 - Background: Studies in animal models of Alzheimer’s disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain. Methods: We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects. Results: APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations 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. Conclusions: 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 absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.
AB - Background: Studies in animal models of Alzheimer’s disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain. Methods: We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects. Results: APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations 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. Conclusions: 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 absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.
KW - Autosomal dominant Alzheimer’s disease
KW - Functional brain imaging
KW - Local field potential (LFP) recordings
KW - Mouse models of Alzheimer’s disease
KW - Translational network neuroscience
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U2 - https://doi.org/10.1186/s13195-023-01287-6
DO - https://doi.org/10.1186/s13195-023-01287-6
M3 - Article
C2 - 37608393
SN - 1758-9193
VL - 15
SP - 1
EP - 21
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 142
ER -