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

GALEANO, PABLO; REYES TOSO, CARLOS; GEVORKIAN, GOAR; MORELLI, LAURA; MARTINO ADAMI, PAMELA V; RABOSSI, ALEJANDRO; RADI, RAFAEL; CUELLO, A CLAUDIO; WALLINGER, MARINA L.; CARDINALI, DANIEL; CASTAÑO, EDUARDO M

Buenos Aires

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

Diet is a modifiable risk factor for Alzheimer?s disease (AD) but the mechanisms linking peripheral metabolism and cognition are unclear. Since it is especially difficult to study long-term effects of energy-dense diet in human subjects at risk for AD, we have chosen McGill-R-Thy1-APP transgenic rats (Tg(+/-)) that capture 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 a Western diet (WD), high in saturated fat and sugar. Our results showed that WD induced a metabolic syndrome and decreased presynaptic bioenergetic parameters without alterations in brain insulin signaling or lipid composition. Furthermore, WD worsened cognition in Tg(+/-) rats, increased amyloidogenic processing of amyloid precursor protein, promoted deposits of pyroglutamate-Aβ, decreased transcript levels of genes involved in neuroprotective pathways and increased nitrated proteins. Our results support the notion that in the presence of early Aβ pathology, diet-induced metabolic dysfunction may contribute as a ?second hit? to impair cognition. Such effect may be partially attributed to dysregulation of neuroprotective metabolic pathways governed by Sirtuin-1 and generation of post-translational modifications of Aβ with pathological properties that may modulate disease progression. This evidence in a rat model of early AD reinforces the implementation of prophylactic interventions in individuals at risk