TY - JOUR

T1 - High-fat diet exacerbates cognitive and metabolic abnormalities in neuronal BACE1 knock-in mice - partial prevention by Fenretinide

AU - Plucinska, Kaja

AU - Mody, Nimesh

AU - Dekeryte, Ruta

AU - Shearer, Kirsty

AU - Mcilroy, George D.

AU - Delibegovic, Mirela

AU - Platt, Bettina

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - beta-Secretase 1

KW - Alzheimer's disease

KW - diabetes

KW - high-fat diet

KW - retinoid

KW - BRAIN INSULIN-RESISTANCE

KW - TRANSGENIC MOUSE MODEL

KW - BODY-MASS INDEX

KW - ALZHEIMERS-DISEASE

KW - INDUCED OBESITY

KW - AMYLOID PATHOLOGY

KW - MEMORY DEFICITS

KW - BETA OLIGOMERS

KW - GENE DELETION

KW - A-BETA

U2 - 10.1080/1028415X.2020.1806190

DO - 10.1080/1028415X.2020.1806190

M3 - Journal article

C2 - 32862802

VL - 25

SP - 719

EP - 736

JO - Nutritional Neuroscience

JF - Nutritional Neuroscience

SN - 1028-415X

IS - 4

ER -