Virtually all adults with Down syndrome (DS) show, by the age of 40 years, the neuropathological changes of Alzheimer¿s disease (AD), with accumulation of senile plaques and neurofibrillary tangles. In addition to these toxic protein deposits, alteration of mitochondria-the powerhouse of the cell- is considered to be a key pathogenic event in the onset of AD neuropathology. Their role may be so critical that an impairment in the mechanism by which cells get rid of the damaged mitochondria has been implicated in the development of this devastating disorder. The mitochondrial quality control is central to maintaining a healthy pool of neurons and any damage to mitochondria might lead to neuronal loss, synaptic damage, and neurodegeneration. If the hypothesis is correct, it could be possible to prevent and/or reverse the typical AD alterations in DS by promoting the destruction of damaged mitochondria. We intend to test this hypothesis in a mouse model of the disease (Ts65Dn), which will allow us to correlate molecular events with cognitive functions. This choice is based on knowledge that AD affects individuals with DS with a very high frequency and at an early age. Although DS is relatively rare, it still represents the largest population in which AD is predictable, which clearly provides a unique opportunity to implement preventive approaches.
Based on parallel and complementary analyses this project aims to: 1) investigate the temporal evolution of the mitochondrial and AD pathological phenotype in Ts65Dn, model of AD in DS; 2) test the hypothesis that a mitophagy-promoting drug is able to rescue mitochondrial abnormalities in Ts65Dn mice thus preventing/slowing the onset of AD neuropathology. If this drug works, it could be used for a clinical trial in the DS population.
In Europe, for 5.2 million births there are 8,000 with DS per year i.e. 16/10,000. Life expectancy of individuals with DS has also increased dramatically to 60 years due to better detection and treatment of congenital heart defects in DS children. The population with DS in Europe, approximately 500,000 individuals, now lives longer and develops DS-associated comorbidities, among which AD is the most frequent. Yet it is the largest population for which we can predict in advance that they will develop AD. Nevertheless, they have not yet been included in clinical trials to prevent and/or treat AD. With this work we want to lay the foundations for such a study, which would likely be of broader interest in case the processes leading to the establishment of the AD phenotype in DS are identical to those of the general population.
A novelty of our approach is that it is focused on the convergence of two central processes in cellular physiology: autophagy and energy conversions. Of great significance is also the opportunity to evaluate the genetic factors and molecular pathways of AD from a new perspective and with new tools at our disposal. We believe that the results obtained can be translated to other neurodegenerative disorders, where mitochondrial deficits appear to be a key pathological aspect. However, our model offers the opportunity to characterize in detail multiple age-dependent processes closely related to mitochondrial network. This is of fundamental importance to set preventive strategies for the elderly population, beyond the limited DS sub-population, thus having the potential to open new frontiers in the field of preventive medicine.
Our working hypothesis is simple and with solid bases. If we prove that it is correct, a reasonable consequence would be to enrol in clinical trials the population of adults with DS who are usually neglected by the national health policy. Even a partial success of our approach can have a significant impact at individual, family and community level. Delaying the onset of the first symptoms and/or slowing the progression of the disease would open up a glimmer of therapeutic approach. One of the drugs we propose to test, metformin, is commonly used for the treatment of diabetes and has mild side effects. Its potential beneficial effects on mitochondrial function have already been demonstrated at the cellular level, yet it has not been tested in the DS population.
The advancement of medical treatment that individuals with DS receive for various complications from which they suffer, including cardiovascular, immunological and oncologic conditions enables them to reach to their 6th decade. It is therefore becoming increasingly common for individuals with DS to integrate in the general population. However, this promoting intact cognitive capacity in DS individuals is imperative to support this unique and important population towards a better integration in society. In addition to this important societal impact, this study can have a significant impact on both direct and in-direct costs involved in health system costs and workdays of family members.
Current drugs used to prevent or delay the onset of dementia have led to limited results. This indicates that the development of new therapeutic approaches is of high importance.
Thus, the results that will emerge from this project are expected to provide an indication for translational approach to the delay of Alzheimer-like dementia in DS.