| Authors |
Niedowicz DM, Reeves VL, Platt TL, Kohler K, Beckett TL, Powell DK, Lee TL,
Sexton TR, Song ES, Brewer LD, Latimer CS, Kraner SD, Larson KL, Ozcan S, Norris
CM, Hersh LB, Porter NM, Wilcock DM, Murphy MP
|
| Submitted By |
Submitted Externally on 11/4/2014 |
| Status |
Published |
| Journal |
Acta neuropathologica communications |
| Year |
2014 |
| Date Published |
|
| Volume : Pages |
2 : 64 |
| PubMed Reference |
24916066 |
| 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/?NLx
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
ß-amyloid (Aß)). 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 Aß
deposition was not significantly increased in the diabetic mice, though overall
expression of presenilin was elevated. Surprisingly, Aß was not deposited in the
vasculature or removed to the plasma, and there was no stimulation of activity
or expression of major Aß-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?NLx 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 Aß 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.
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