Abstract
Objective:The beta-site APP-cleaving enzyme 1 (BACE1) is a rate-limiting step in beta-amyloid (A beta) production in Alzheimer's disease (AD) brains, but recent evidence suggests that BACE1 is also involved in metabolic regulation. Here, we aimed to assess the effects of highfat diet (HFD) on metabolic and cognitive phenotypes in the diabetic BACE1 knock-in mice (PLB4) and WT controls; we additionally examined whether these phenotypes can be normalized with a synthetic retinoid (Fenretinide, Fen) targeting weight loss.
Methods:Five-month old male WT and PLB4 mice were fed either (1) control chow diet, (2) 45%-saturated fat diet (HFD), (3) HFD with 0.04% Fen (HFD + Fen) or (4) control chow diet with 0.04% Fen (Fen) for 10 weeks. We assessed basic metabolic parameters, circadian rhythmicity, spatial habituation (Phenotyper) and working memory (Y-maze). Hypothalami, forebrain and liver tissues were assessed using Western blots, qPCR and ELISAs.
Results:HFD feeding drastically worsened metabolism and induced early mortality (-40%) in otherwise viable PLB4 mice. This was ameliorated by Fen, despite no effects on glucose intolerance. In HFD-fed WT mice, Fen reduced weight gain, glucose intolerance and hepatic steatosis. The physiological changes induced in WT and PLB4 mice by HFD (+/-Fen) were accompanied by enhanced cerebral astrogliosis, elevated PTP1B, phopsho-eIF2 alpha and altered hypothalamic transcription of Bace1, Pomc and Mc4r. Behaviourally, HFD feeding exacerbated spatial memory deficits in PLB4 mice, which was prevented by Fen and linked with increased full-length APP, normalized brain A beta*56 oligomerization and astrogliosis. Conclusions:HFD induces early mortality and worsened cognition in the Alzheimer's-like BACE1 mice- partial prevention was achieved with Fenretinide, without improvements in glucose homeostasis.
| Original language | English |
|---|---|
| Pages (from-to) | 719-736 |
| Number of pages | 18 |
| Journal | Nutritional Neuroscience |
| Volume | 25 |
| Issue number | 4 |
| Early online date | 29 Aug 2020 |
| DOIs | |
| Publication status | Published - Apr 2022 |
Bibliographical note
Funding:KP was sponsored by a generous donation from R. Simcox, Romex Oilfield Chemicals. We would additionally like to acknowledge contributions from the Scottish Alzheimer’s Research UK (ARUK-NC2019-SCO) network as well as British Heart Foundation (BHF, PG/14/43/30889 and PG/11/8/28703) and Diabetes UK (DUK, BDA/R008/0003597) who sponsored the research in BP and MD laboratories, respectively. NM was funded by a British Heart Foundation Intermediate Fellowship (FS/09/026); RD received support from an Institute of Medical Sciences PhD studentship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant and GDM was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) doctoral training grant.
Data Availability Statement
The data sets generated during and/or analysed during the current study are available from the corresponding authors on request.Keywords
- β-Secretase 1
- Alzheimer’s disease
- diabetes
- high-fat diet
- retinoid
- beta-Secretase 1
- ALZHEIMERS-DISEASE
- MEMORY DEFICITS
- BRAIN INSULIN-RESISTANCE
- AMYLOID PATHOLOGY
- BETA OLIGOMERS
- A-BETA
- BODY-MASS INDEX
- GENE DELETION
- TRANSGENIC MOUSE MODEL
- Alzheimer's disease
- INDUCED OBESITY
