TY - JOUR
T1 - Cognitive decline in diabetic mice predisposed to Alzheimer’s disease is greater than in wild type
AU - Carús-Cadavieco, Marta
AU - López, Inés Berenguer
AU - Montoro Canelo, Alba
AU - Serrano-Lope, Miguel A.
AU - González de la Fuente, Sandra
AU - Aguado, Begoña
AU - Fernández-Rodrigo, Alba
AU - Saido, Takaomi C.
AU - García, Ana Frank
AU - Venero, César
AU - Esteban, José A.
AU - Guix, Francesc
AU - Dotti, Carlos G.
N1 - Funding Information:
The next-generation sequencing data analysis has been performed by the Genomics and next-generation sequencing Core Facility at the Centro de Biología Molecular Severo Ochoa (CBM, CSIC-UAM), which is part of the CEI UAM+CSIC, Madrid, Spain—http://www.cbm.uam.es/genomica. The confocal microscopy analysis was performed at the Confocal Microscopy Facility of CBM. We would also like to thank Esperanza López-Merino from Jose A Esteban’s laboratory (CBM), for her advice with the electrophysiology experiments. Finally, we thank Mercedes Hernández del Cerro for assisting us with the genotyping of the hAPP NL/F colony. This work was partially supported by grant PID2019-104389RB-I00 funded by MCIN/AEI/10.13039/ 501100011033 and “ERDF A way of making Europe” and by the European Union NextGenerationEU/PRTR CSIC’s Interdisciplinary Thematic Platform PTI+ NEURO-AGING, both to CG Dotti, Marie Skłodowska-Curie Actions—Individual Fellowship (T2DM and AD, EU 708152) to F Guix and EU JPND “EpiAD” Grant to A Frank García and CG Dotti. M Carús-Cadavieco is the recipient of a Juan de la Cierva Formación Postdoctoral Fellowship (FJC2018-036152-I, MCIN/AEI).
Publisher Copyright:
© 2023 Carús-Cadavieco et al.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - Brain insulin-resistance
KW - Dendritic spines
KW - Gamma-secretase
KW - Mouse models
KW - Oxidative stress
KW - Tau-protein
KW - Memory
KW - Diet
KW - App
KW - Impairment
UR - http://www.scopus.com/inward/record.url?scp=85152531870&partnerID=8YFLogxK
UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;KeyUT=000972403400002
UR - http://hdl.handle.net/20.500.14342/4658
U2 - 10.26508/lsa.202201789
DO - 10.26508/lsa.202201789
M3 - Article
C2 - 37059474
AN - SCOPUS:85152531870
SN - 2575-1077
VL - 6
JO - Life Science Alliance
JF - Life Science Alliance
IS - 6
M1 - e202201789
ER -
