Cognitive decline in diabetic mice predisposed to Alzheimer’s disease is greater than in wild type

Marta Carús-Cadavieco, Inés Berenguer López, Alba Montoro Canelo, Miguel A. Serrano-Lope, Sandra González de la Fuente, Begoña Aguado, Alba Fernández-Rodrigo, Takaomi C. Saido, Ana Frank García, César Venero, José A. Esteban, Francesc Guix, Carlos G. Dotti

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1 Citació (Scopus)


In this work, we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in middle-aged hAPP NL/F mice, a preclinical model of Alzheimer’s disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.

Idioma originalAnglès
Número d’articlee202201789
Nombre de pàgines20
RevistaLife Science Alliance
Estat de la publicacióPublicada - de juny 2023


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