Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer’s Disease Stage in APP/PS1 Mice

Article type: Research Article

Authors: Ettcheto, Miren^{a; c} | Petrov, Dmitry^{a; c} | Pedrós, Ignacio^{b; c} | Alva, Norma^d | Carbonell, Teresa^d | Beas-Zarate, Carlos^{f; g} | Pallas, Merce^{a; c} | Auladell, Carme^e | Folch, Jaume^{b; c; 1} | Camins, Antoni^{a; c; 1; *}

Affiliations: [a] Unitat de Farmacologia i Farmacognòsia, Institut de Neurociencias, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain | [b] Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus (Tarragona), Spain | [c] Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain | [d] Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain | [e] Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain | [f] Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, CIBO, IMSS, México | [g] Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, México

Correspondence: [*] Correspondence to: Antoni Camins PhD, Unitat de Farmacologia i Farmacognosia, Facultat de Farmàcia, Universitat de Barcelona, Avda/Diagonal 643, E-08028 Barcelona, Spain. Tel.: +34 93 4024531; Fax: +34 934035982; E-mail: [email protected].

Note: [1] Co-Senior Authors.

Abstract: Alzheimer’s disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

Keywords: Alzheimer’s disease, APPSwe/PS1dE9, hippocampus, insulin receptor, mitochondria, tau

DOI: 10.3233/JAD-160150

Journal: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 233-251, 2016