AD-AP

Alzheimer's disease (AD) is the leading cause of dementia worldwide, but the underlying pathophysiological mechanisms are still poorly understood. According to the ‘amyloid cascade’ hypothesis, the accumulation of Aß peptides is the condition that induces the development of neurofibrillary degeneration and hence neuronal death. However, although recent clinical trials of anti-Aß immunotherapies support this hypothesis, it has been regularly modified to reflect advances in our understanding of AD. The genetic component of AD is particularly important and our knowledge of the genetic drivers of this disease has led us to revisit this hypothesis. We propose that dysfunction of cell adhesion pathways at synapses, potentially through alterations in the mechano-transduction properties of APP, is involved in the development of AD. These alterations lead to synaptic and then neuronal dysfunction and ultimately promote hyperphosphorylation of the tau protein and neurodegeneration. Our aim is therefore to evaluate this hypothesis by: (i) delineating the signaling pathways associated with cell adhesion that depend on the mechano-transduction properties of APP (ii) validating the genetic risk factors for AD in these signaling pathways as modulators of APP-dependent synaptic functions (iii) defining the impact of genetic risk factors on tau/A?-associated synaptotoxicity and AD hallmarks. In conclusion, our project proposes to study an original hypothesis based on a genetic-dependent synaptic dysfunction in AD via adhesion pathways linked to APP and may therefore potentially offer new therapeutic approaches.