PreSSAD awarded, will study early presynaptic AD biomarkers

A major endeavour in research on Alzheimer’s disease (AD) is to characterize presymptomatic subthreshold changes in the brain that are unnoticeable to the patient. Studies on post-mortem brains correspond to the final stage of the disease and do not capture dynamic events that lead to synapse loss, and in particular fall short in providing information on impaired synaptic function, which precede synapse loss. This project aims at identifying presymptomatic synaptic deficits in the context of the human AD pathology. Elucidating events and mechanisms leading from early synaptic dysfunction to axonal degeneration and neuronal death and contribute to new prediagnostic markers of synaptic dysfunction in AD.
Whereas previous studies have mainly used animal models of AD pathology, we will take advantage of innovative methodologies using human materials, including CSF from presymptomatic AD patients, iPSCs-derived human neurons either in 2D culture, in 3D cerebral organoids or grafted in newborn mice, as well as organotypic human cortical slices derived from surgical resections. Here we combine the expertise of five groups spanning from the identification of biomarkers in preclinical AD cohorts to human synaptic biology. A major originality of the proposal is in the use of innovative human biological samples to assess the early physiopathological stages of synapse dysfunction and loss. We analyze quantitative proteomics from human samples, study early events in iPSCs-derived neurons in 2D and 3D cultures from FAD, SAD and MCI patients and matching-control, describe early events leading to synapse loss in human derived neurons grafted in newborn mice and implement gene targeting, patch-clamp recordings and single-cell transcriptomics in cultured human cortical slices obtained from surgical resections.