title: Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia.
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 APPΔNL/ΔNLx PS1P264L/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 APPΔNLx PS1P264L 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.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Niedowicz
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Reeves
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Platt
authors.forename: Katharina
authors.initials: K
authors.lastname: Kohler
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.forename: David K
authors.initials: DK
authors.lastname: Powell
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Lee
authors.forename: Travis R
authors.initials: TR
authors.lastname: Sexton
authors.forename: Eun Suk
authors.initials: ES
authors.lastname: Song
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Brewer
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Latimer
authors.forename: Susan D
authors.initials: SD
authors.lastname: Kraner
authors.forename: Kara L
authors.initials: KL
authors.lastname: Larson
authors.forename: Sabire
authors.initials: S
authors.lastname: Ozcan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.forename: Nada M
authors.initials: NM
authors.lastname: Porter
authors.forename: Donna M
authors.initials: DM
authors.lastname: Wilcock
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, 800 S, Limestone, Sanders Brown 211, Lexington, KY 40536-0230, USA. mpmurp3@email.uky.edu.
authors.forename: Michael Paul
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D003072:Cognition Disorders / Q000097:blood / Q000209:etiology* / Q000235:genetics; D015140:Dementia, Vascular / Q000097:blood / Q000150:complications* / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000097:blood; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015260:Neprilysin / Q000378:metabolism; D009767:Obesity, Morbid / Q000097:blood / Q000150:complications* / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D020738:Leptin; C508853:PSEN1 protein, human; D053764:Presenilin-1; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D015260:Neprilysin