title: 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.
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.
authors.affiliation: Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Pamela V
authors.initials: PV
authors.lastname: Martino Adami
authors.affiliation: Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir, IIBBA-CONICET, Argentina; ININCA-UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Galeano
authors.affiliation: Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Wallinger
authors.affiliation: Department of Biochemistry, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República (UdeLaR), Uruguay.
authors.forename: Celia
authors.initials: C
authors.lastname: Quijano
authors.affiliation: Laboratory of Biochemistry and Molecular Biology of Development, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rabossi
authors.affiliation: Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Eleonora S
authors.initials: ES
authors.lastname: Pagano
authors.affiliation: Centro de Neuropsiquiatría y Neurología de la Conducta (CENECON), Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Natividad
authors.initials: N
authors.lastname: Olivar
authors.affiliation: Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Reyes Toso
authors.affiliation: Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cardinali
authors.affiliation: Centro de Neuropsiquiatría y Neurología de la Conducta (CENECON), Unidad Académica II, Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: Luis I
authors.initials: LI
authors.lastname: Brusco
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Carmo
authors.affiliation: Department of Biochemistry, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República (UdeLaR), Uruguay.
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico.
authors.forename: Goar
authors.initials: G
authors.lastname: Gevorkian
authors.affiliation: Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Canada.
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
authors.affiliation: Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir, IIBBA-CONICET, Argentina. Electronic address: lmorelli@leloir.org.ar.
authors.forename: Laura
authors.initials: L
authors.lastname: Morelli
mesh_terms: D050154:Adiposity; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003071:Cognition; D066273:Diet, Western / Q000009:adverse effects*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D011761:Pyrrolidonecarboxylic Acid
keywords: APP processing and pyroglutamate-Aβ; Bioenergetic Health Index; Cognitive decline; Dietary fat; Early Alzheimer; Inflammation