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Differential Effects of Human P301L Tau Expression in Young versus Aged Mice

The greatest risk factor for developing Alzheimer’s disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utiliz...

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Autores principales: Hunsberger, Holly C., Setti, Sharay E., Rudy, Carolyn C., Weitzner, Daniel S., Pfitzer, Jeremiah C., McDonald, Kelli L., Hong, Hao, Bhattacharya, Subhrajit, Suppiramaniam, Vishnu, Reed, Miranda N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583766/
https://www.ncbi.nlm.nih.gov/pubmed/34769068
http://dx.doi.org/10.3390/ijms222111637
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author Hunsberger, Holly C.
Setti, Sharay E.
Rudy, Carolyn C.
Weitzner, Daniel S.
Pfitzer, Jeremiah C.
McDonald, Kelli L.
Hong, Hao
Bhattacharya, Subhrajit
Suppiramaniam, Vishnu
Reed, Miranda N.
author_facet Hunsberger, Holly C.
Setti, Sharay E.
Rudy, Carolyn C.
Weitzner, Daniel S.
Pfitzer, Jeremiah C.
McDonald, Kelli L.
Hong, Hao
Bhattacharya, Subhrajit
Suppiramaniam, Vishnu
Reed, Miranda N.
author_sort Hunsberger, Holly C.
collection PubMed
description The greatest risk factor for developing Alzheimer’s disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human tau transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals.
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spelling pubmed-85837662021-11-12 Differential Effects of Human P301L Tau Expression in Young versus Aged Mice Hunsberger, Holly C. Setti, Sharay E. Rudy, Carolyn C. Weitzner, Daniel S. Pfitzer, Jeremiah C. McDonald, Kelli L. Hong, Hao Bhattacharya, Subhrajit Suppiramaniam, Vishnu Reed, Miranda N. Int J Mol Sci Article The greatest risk factor for developing Alzheimer’s disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human tau transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals. MDPI 2021-10-28 /pmc/articles/PMC8583766/ /pubmed/34769068 http://dx.doi.org/10.3390/ijms222111637 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hunsberger, Holly C.
Setti, Sharay E.
Rudy, Carolyn C.
Weitzner, Daniel S.
Pfitzer, Jeremiah C.
McDonald, Kelli L.
Hong, Hao
Bhattacharya, Subhrajit
Suppiramaniam, Vishnu
Reed, Miranda N.
Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title_full Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title_fullStr Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title_full_unstemmed Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title_short Differential Effects of Human P301L Tau Expression in Young versus Aged Mice
title_sort differential effects of human p301l tau expression in young versus aged mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583766/
https://www.ncbi.nlm.nih.gov/pubmed/34769068
http://dx.doi.org/10.3390/ijms222111637
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