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.
