Energy-dense diet worsens early cognitive impairment through dysregulation of neuroprotective pathways and pyroglutamate-Aβ generation: evidence from a transgenic Alzheimer rat model

GALEANO P; REYES TOSO C; GEVORKIAN G; MORELLI L; MARTINO ADAMI P; RABOSSI A; RADI R; CUELLO AC; WALLINGER M; CARDINALI D; CASTAÑO EM

Buenos Aires

Congreso; 2nd Federation of Latin American and Caribbean Societies for Neurosciences (FALAN) Congress; 2016

Federation of Latin American and Caribbean Societies for Neurosciences

Diet is amodifiable risk factor for Alzheimer?s disease (AD) but the mechanisms linkingperipheral metabolism and cognition are unclear. Since it is especiallydifficult to study long-term effects of energy-dense diet in human subjects atrisk for AD, we have chosen McGill-R-Thy1-APP transgenic rats (Tg(+/-)) thatcapture the full array of presymptomatic AD pathology. Wild-type and Tg(+/-)rats were exposed from 35 days to 6 months of age to a standard diet or aWestern diet (WD), high in saturated fat and sugar. Our results showed that WDinduced a metabolic syndrome and decreased presynaptic bioenergetic parameterswithout alterations in brain insulin signaling or lipid composition.Furthermore, WD worsened cognition in Tg(+/-) rats, increased amyloidogenicprocessing of amyloid precursor protein, promoted deposits of pyroglutamate-Aβ,decreased transcript levels of genes involved in neuroprotective pathways andincreased nitrated proteins. Our results support the notion that in thepresence of early Aβ pathology, diet-induced metabolic dysfunction maycontribute as a ?second hit? to impair cognition. Such effect may be partiallyattributed to dysregulation of neuroprotective metabolic pathways governed bySirtuin-1 and generation of post-translational modifications of Aβ withpathological properties that may modulate disease progression. This evidence ina rat model of early AD reinforces the implementation of prophylacticinterventions in individuals at risk.