Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer's disease is associated to neurotoxic Aβ species and independent of neuroinflammation

MARTINO ADAMI P; QUIJANO C; OLIVAR, N; BRUSCO LI; GEVORKIAN, G; MORELLI, L; GALEANO, P.; WALLINGER, ML; RABOSSI, A; PAGANO, ES; REYES TOSO, C; CARDINALE, D; DO CARMO, S; RADI, R; CASTAÑO, E.M.; CUELLO, C

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2017 vol. 1863 p. 731 - 743

0925-4439

Diet is a modifiable risk factor for Alzheimer´s disease (AD), but the mechanisms linking alterations in peripheral metabolism and cognition remain unclear. Since it is especially difficult to study long-termeffects of high-energy diet in individuals at risk for AD, we addressed this question by using the McGill-R-Thy1-APP transgenic rat model (Tg(+/−)) that mimics presymptomatic AD. Wild-type and Tg(+/−) ratswere exposed during 6 monthsto a standard diet or aWestern diet(WD), high in saturated fat and sugar. Results from peripheral and hippocampal biochemical analysis and in situ respirometry showed that WD induced a metabolic syndrome and decreased presynaptic bioenergetic parameters without alterations in hippocampal insulin signaling or lipid composition. Cognitive tests, ELISA multiplex,Western blot, immunohistochemistry and RT-qPCR indicated that WD worsenedcognition in Tg(+/−) rats, increased hippocampal levels of monomeric Aβ isoforms and oligomeric species, promoted deposits of N-Terminal pyroglutamate-Aβ (AβN3(pE)) in CA1 pyramidal neurons and interneurons, decreased transcript levels of genes involved in neuroprotective pathways such as Sirtuin-1 and increased nitrated proteins. Our results support the concept that in the presence of early Aβ pathology, diet-induced metabolicdysfunctions may contribute as a ?second hit? to impair cognition. Noteworthy, such effect is not mediated by higher microglia activation or disruption of blood brain barrier. However, it may be attributed to increased amyloidogenic processing of amyloid precursor protein, generation of AβN3(pE) and dysregulation of pathways governed by Sirtuin-1. This evidence reinforces the implementation of prophylactic interventions in individualsat risk for AD.