Obesity and Diabetes Cause Cognitive Dysfunction in the Absence of Accelerated β-Amyloid Deposition in a Novel Murine Model of Mixed or Vascular Dementia

Authors

Dana M. Niedowicz, University of KentuckyFollow
Valerie L. Reeves, University of Kentucky
Thomas L. Platt, University of Kentucky
Katharina Kohler, University of KentuckyFollow
Tina L. Beckett, University of KentuckyFollow
David K. Powell, University of Kentucky
Tiffany L. Lee, University of KentuckyFollow
Travis R. Sexton, University of KentuckyFollow
Eun Suk Song, University of KentuckyFollow
Lawrence D. Brewer, University of KentuckyFollow
Caitlin S. Latimer, University of Kentucky
Susan D. Kraner, University of KentuckyFollow
Kara L. Larson, University of Kentucky
Sabire Özcan, University of KentuckyFollow
Christopher M. Norris, University of KentuckyFollow
Louis B. Hersh, University of KentuckyFollow
Nada M. Porter, University of KentuckyFollow
Donna M. Wilcock, University of KentuckyFollow
Michael Paul Murphy, University of KentuckyFollow

Abstract

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APP^ΔNL/ΔNLx PS1^P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APP^ΔNLx PS1^P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Document Type

Article

Publication Date

6-10-2014

Notes/Citation Information

Published in Acta Neuropathologica Communications, v. 2, article 64, p. 1-17.

© Niedowicz et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1186/2051-5960-2-64

Funding Information

This work was funded by the NIH (NS058382, NS083692, GM103486, DK020579), the Coins for Alzheimer’s Research Trust (CART), the American Heart Association (13IRG14330016) and the Alzheimer’s Association (IIRG-10-172905).

Repository Citation

Niedowicz, Dana M.; Reeves, Valerie L.; Platt, Thomas L.; Kohler, Katharina; Beckett, Tina L.; Powell, David K.; Lee, Tiffany L.; Sexton, Travis R.; Song, Eun Suk; Brewer, Lawrence D.; Latimer, Caitlin S.; Kraner, Susan D.; Larson, Kara L.; Özcan, Sabire; Norris, Christopher M.; Hersh, Louis B.; Porter, Nada M.; Wilcock, Donna M.; and Murphy, Michael Paul, "Obesity and Diabetes Cause Cognitive Dysfunction in the Absence of Accelerated β-Amyloid Deposition in a Novel Murine Model of Mixed or Vascular Dementia" (2014). Sanders-Brown Center on Aging Faculty Publications. 50.
https://uknowledge.uky.edu/sbcoa_facpub/50