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Report

Teaser, summary, work performed and final results

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)

Teaser

Summary

Alzheimerâ€™s Disease (AD) is a devastating neurodegenerative disease and the main cause of human dementia. No effective treatment exist for the disease. AD is histophatologically characterized by the presence of extraneuronal senile plaques and intraneuronal neurofibrillary tangles (NFT), composed of Amyloid beta-peptide (Abeta) and deposits of tau protein, respectively. Mostly based on studies of families with inherited AD (FAD), it is assumed that abnormal Abeta generation is the initial trigger of the disease process (the amyloid hypothesis). Assuming that an abnormal production of Abeta is also responsible in the so-called late onset AD (LOAD), which accounts for more than 90% of all cases, it remains to be defined how life conditions that predispose to disease lead to this biochemical abnormality. Although aging is the main cause of AD, age per se is not sufficient to develop the disease: age-related comorbid states are thought to be required. Of these, type II diabetes mellitus (T2DM), a metabolic disorder highly prevalent in the adulthood, has extensively been associated to a higher risk of developing AD. T2DM is characterized by hyperglycemia, insulin resistance and a 10 years-shorter life expectancy. However, this age-related comorbid state is not enough to trigger AD and the individual genetic background must play an important role. In this sense, Genome Wide Associated Studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) which are more frequently found in the group of either healthy or AD people. The study of the DNA sequences involving these SNPs has allowed us to identify new genetic risk factors for the disease. Again, the low contribution of the risk provided for each individual SNPs points out to the necessary co-existence of the individual genetic background with age-related comorbid states in order to create a pathological framework sufficient to trigger AD, such as abnormal increase in the amyloidogenic pathway or a higher susceptibility of neurons to metabolic stress. In the present study, we induced type II diabetes mellitus to a preclinical AD mouse model that expresses endogenous levels of a mutated version of the human APP gene (APPNL), generating high levels of the human Abeta peptide. Despite the high levels of the Abeta produced, these mice do not form amyloid plaques in the brain and do perform normally in behavioral test.

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.

Work performed

- We induced T2DM, a common age-related comorbid state associated to a higher risk of developing Alzheimerâ€™s disease (AD), to an AD preclinical mouse model (APPNL) with the objective of triggering AD-associated pathological changes in order to emulate the onset of the disease in humans and investigate which are the molecular alterations responsible for the pathology. However, the induction of T2DM on APPNL mice did not trigger pathologically relevant alterations during the development of this project, besides the fact that APPNL mice produce high levels of human Abeta peptide.

- 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.

DISSEMINATION

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 (â€Madrid Contigoâ€ of Telemadrid (Spain)).

Final results

AD is the most common cause of dementia and no effective treatments exist. Despite the multi-factorial origin of AD, the amyloid cascade hypothesis states that the accumulation of Abeta peptide in the brain is the triggering factor of a series of downstream events that lead to cognitive decline in AD. However, APPNL knockin mice that produce high levels of human Abeta peptide do not show neurodegeneration. At the theoretical level, it implies that Abeta per se is not enough to trigger neurodegeneration, meaning that other factors such as environmental factors, comorbid states or alteration of gene expression may be required or modulate the triggering of the pathology or prevent its appearance. The induction of a metabolic stress like T2DM in APPNL mice was not enough to trigger an AD-like pathology. However, we found out that several genes/proteins that are associated to neuroprotective roles are up-regulated in the brain of APP knockin mice or in brain-derived EVs, and may be protecting neurons against Abeta-induced toxicity. On the other hand, the lack of a good AD animal model that recapitulates several aspects of the disease is a limiting factor for the development of effective therapies that successfully stop or slow down cognitive decline in AD patients. In this sense, the down-regulation of one or several of the protective genes and proteins found overexpressed in the brain of the APPNL mice could bring up an AD phenotype in this mouse model.