Alzheimer’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.
