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Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of epis...

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Autores principales: Islam, Anam, Saito, Takashi, Saido, Takaomi, Ali, Afia B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Academic Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439011/
https://www.ncbi.nlm.nih.gov/pubmed/35292192
http://dx.doi.org/10.1016/j.semcdb.2022.03.001
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author Islam, Anam
Saito, Takashi
Saido, Takaomi
Ali, Afia B.
author_facet Islam, Anam
Saito, Takashi
Saido, Takaomi
Ali, Afia B.
author_sort Islam, Anam
collection PubMed
description The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APP(NL-F/NL-F), and APP(NL-F)/MAPT(HTAU) and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.
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spelling pubmed-104390112023-08-20 Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease Islam, Anam Saito, Takashi Saido, Takaomi Ali, Afia B. Semin Cell Dev Biol Orginal Research Article The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APP(NL-F/NL-F), and APP(NL-F)/MAPT(HTAU) and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD. Academic Press 2023-04 /pmc/articles/PMC10439011/ /pubmed/35292192 http://dx.doi.org/10.1016/j.semcdb.2022.03.001 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Orginal Research Article
Islam, Anam
Saito, Takashi
Saido, Takaomi
Ali, Afia B.
Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title_full Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title_fullStr Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title_full_unstemmed Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title_short Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease
title_sort presubiculum principal cells are preserved from degeneration in knock-in app/tau mouse models of alzheimer’s disease
topic Orginal Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439011/
https://www.ncbi.nlm.nih.gov/pubmed/35292192
http://dx.doi.org/10.1016/j.semcdb.2022.03.001
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