Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia

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

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 ∆NL/∆NL x 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 ∆NL x 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.

Original languageEnglish
Article number64
JournalActa neuropathologica communications
Volume2
Issue number1
DOIs
StatePublished - Jan 27 2014

Bibliographical note

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). Special thanks to Dr. Shaun Carlson for assistance with confocal pictures Alexandra Sutphin for assistance with histological quantitation, and Dr. Pete Nelson for neuropathological diagnoses. The authors declare no competing financial interests.

Publisher Copyright:
© 2014 Niedowicz et al.; licensee BioMed Central Ltd.

Keywords

  • Alzheimer's disease
  • Dementia
  • Diabetes
  • Obesity
  • Stroke

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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