Periodic Reporting for period 1 - T2DM and AD (Study of the interaction between metabolic stress and a specific genetic background on the contribution of sporadic Alzheimer's Disease)
Reporting period: 2017-04-01 to 2019-03-31
The present project aims to assess the consequences of a systemic disorder like T2DM, a well characterized age-related pathological state, in the brains of wild type mice and in mice bearing genetic deficiencies, in order to emulate human AD-linked genetic predisposition backgrounds. While, as I described above, the existence of an age-associated comorbid state like T2DM is not sufficient to produce LOAD, it is certainly possible that T2DM can trigger brain disease if occurring in a genetically predisposed individual, conceivably through changes in the expression of particular set of genes in certain brain areas (disease susceptible). To test these premises is the aim of this application.
- Then we investigated the up-regulation of protective mechanisms in the brain of APPNL mice that can counteract the toxicity induced by the Abeta peptide. We found out an up-regulation of genes related to axonal plasticity and myelin formation in the brain of APPNL mice compared to the WT group, which could confer protection against Abeta-induced axonopathy. On the other hand, we determined that extracellular vesicles (EVs) secreted by brain cells of APPNL mice, contain high levels of proteins related to neuronal plasticity, protein homeostasis and neuroprotection. EVs have an essential role in cell-to-cell communication and can deliver their cargo to neighbouring cells where they may exert their protection. We propose that these up-regulated molecular pathways in the brain of APPNL mice may confer protection against Abeta and provide useful information on genes/proteins that should be potentiated in AD patients to prevent pathological events, thus offering clues on novel therapeutical approaches. On the other hand, the down-regulation of one or several genes found to potentially protect APPNL mice may offer a better AD mouse model without the inconvenients present in transgenic AD mouse models.
There are now two manuscripts under preparation with the results obtained during the action. One manuscript is about the absence of an AD-like phenotype in APPNL mice exposed to metabolic stress, and the potential protective mechanisms operating in this particular AD mouse model. The other manuscript is about the mechanisms inducing higher secretion of EVs during neuronal aging. On the other hand, a paper has been published during the development of the project (Guix and Dotti, EMBO Mol Med, 2018), where funding from this grant is specifically mentioned. The work was presented as a lecture during the Special Seminar Series of CBM (Madrid) and during the forecast of a TV program (”Madrid Contigo” of Telemadrid (Spain)).