DiaAD (On the mechanisms behind type 2 diabetes-induced cognitive

This project is funded by a the Ministery of Science and Research as a Generación del Conocimiento Project alongside CSIC.

There are several risk factors associated with the sporadic forms of Alzheimer’s disease (AD), or late onset Alzheimer’s disease (LOAD). While ageing is a strong factor, it is not, per se, sufficient, as it “only” occurs in a less than a third of the aged population. What then makes that certain old individuals develop this disease? Thanks to genetic and epigenetic studies we now see sporadic AD as the consequence of the interaction between multiple genes (i.e., polygenic) and environmental factors (i.e. complex trait-disease). In this scenario, none of these factors individually (genemutation/polymorphism or environmental insult) are necessary nor sufficient to cause the disease and the probability of developing LOAD is the consequence of the weighted combination of genetic variants (i.e., polygenic scores) and environmental factors. One well-characterized genetic risk factors for LOAD is the presence of the ApoE4 allele, which increases the risk and advances the age of initiation2. Besides these factors, another risk factor for LOAD is diabetes. The general objective of this proposal is twofold: i) to determine the cause of the greater susceptibility of mice with hereditary predisposition to Alzheimer’s disease to develop disease signs and symptoms when they suffer from Type 2 Diabetes, and ii) through what mechanisms.
The specific objectives of this proposal are: 1) To investigate to which extent is the formation of membrane pores by Aß oligomers (AßOs) responsible for the greater predisposition of hAPP NL/F mice to suffer cognitive disorders by T2DM.
2) To investigate to which extent are the decreased levels of HIF-3α and/or the increased levels of Irf7 responsible for T2DM-induced cognitive impairment in hAPP NL/F mice.
3) To determine which of the transcriptomic changes produced by T2DM in the brain of hAPP NL/F mice can be detected in the bloodstream of affected mice and can become a disease predictive/progression biomarker.