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Objective:  The β-site APP-cleaving enzyme 1 (BACE1) is a rate-limiting step in β-amyloid (Aβ) 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-eIF2α 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 Aβ*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.

High-fat diet exacerbates cognitive and metabolic abnormalities in neuronal BACE1 knock-in mice – partial prevention by Fenretinide