Nanoscale rearrangement of APP organization as a therapeutic target for Alzheimer's disease.

Despite the importance of canonical processing of Amyloid Precursor Protein at synapses as a major risk factor for the development of Alzheimer's Disease, there have been very little progress on designing effective therapeutic paradigms targeting it. Majority of the drugs developed or under clinical evaluation focus on the clearance of the detrimental proteoforms or secretases involved in the proteolysis of APP. The lack of interventions targeting APP is in part due to the lack of information in understanding the fine organization of APP and the chemical map of its association with subsynaptic functional zones of the synapse. The recent advances to evaluate the molecular organization of synapses allows us to readdress the need for designing tools to target the full-length APP. Here, we describe the potential role of nanoscale segregation of synaptic APP and how this organization influences the local processing of APP in different subsynaptic compartments opening avenues for early intervention strategies. We envision the need to design smart molecules which would interfere with the real-time chemical composition and physical properties of APP at nanoscale. These tools could alter the balance of proteoforms generated and/or enhance the proteolysis by selective secretases to reduce the toxic products formed through amyloidogenic pathway. We believe that such an approach would be rational to treat or delay the onset of neurodegenerative diseases like AD.