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. 2017 Mar;1863(3):731-743.
doi: 10.1016/j.bbadis.2016.12.014. Epub 2016 Dec 27.

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

Pamela V Martino Adami  1 , Pablo Galeano  2 , Marina L Wallinger  3 , Celia Quijano  4 , Alejandro Rabossi  5 , Eleonora S Pagano  3 , Natividad Olivar  6 , Carlos Reyes Toso  3 , Daniel Cardinali  3 , Luis I Brusco  6 , Sonia Do Carmo  7 , Rafael Radi  4 , Goar Gevorkian  8 , Eduardo M Castaño  1 , A Claudio Cuello  7 , Laura Morelli  9
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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

Pamela V Martino Adami et al. Biochim Biophys Acta Mol Basis Dis. 2017 Mar.
Free article

Abstract

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-term effects 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(+/-) rats were exposed during 6months to a standard diet or a Western 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 worsened cognition 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 metabolic dysfunctions 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 individuals at risk for AD.

Keywords: APP processing and pyroglutamate-Aβ; Bioenergetic Health Index; Cognitive decline; Dietary fat; Early Alzheimer; Inflammation.

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