Alterazioni sinaptiche nella malattia di Alzheimer: dalla generazione di nuovi modelli in vitro all'identificazione di nuovi target (SynAD)

At the moment, Alzheimer's disease (AD) represents one of the largest unmet medical need and places a considerable and increasing burden on patients, caregivers and society since no cure is available. Substantial data indicate accumulation of Aß in the brain, particularly in its non-fibrillar soluble oligomeric forms, as the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles and synapse loss, is considered a

downstream consequence of Aß deposition and it was proposed to result from an imbalance between Aß production and its clearance. Aß derives from the concerted action of ß-secretase, which mediates the Amyloid Precursor Protein (APP) shedding at Aß N-terminus, and gamma-secretase, responsible for APP C-terminal stub cleavage. Alternatively, APP processing is exerted by ADAM10, A Disintegrin And Metalloproteinase family member, whose cleavage on APP prevents Aß formation. Preventing Aß production through an enhancement of ADAM10 cleavage on APP, at the expense of ß-secretase, might be a potentially effective way of addressing the problem of AD therapy. Evidences obtained using transgenic mice validate ADAM10 activation as a viable therapeutic opportunity that can antagonize brain Aß accumulation. To address this issue, we will study interactions between ADAM10 and its potential sorting partners, since ADAM10 processing on APP occurs when both proteins are at the plasma membrane. In our lab, we have already demonstrated, both in vitro and in vivo, that ADAM10 synaptic localization is necessary for its non-amyloidogenic cleavage of APP and that its interaction with SAP97, a scaffold protein of the MAGUK family, is responsible for its synaptic localization. ADAM10/SAP97 complex relevance has also been validated in human AD pathogenesis. Now, we would like to further investigate in minute details ADAM10 membrane localization mechanisms as a potential way of modulating its activity.

Thus, specific aims of this Unit will be:

° To characterize cellular and molecular mechanisms governing ADAM10 synaptic trafficking/localization and activity, through validation of key protein partners of

the enzyme

° To study the reciprocal interaction between activity-dependent plasticity and synaptic localization/activity of ADAM10

° To test, both in transgenic and non transgenic models of AD, phenotypic rescue through activation of ADAM10 synaptic localization and activity

° To characterize biochemically and morphologically specific AD-patients derived pluripotent stem cells obtained from fibroblast of AD patients and to study here

spine morphology and synaptic strength changes.

Therefore, this project might highlight new molecular mechanisms involved in AD pathogenesis and might suggest new potential therapeutic approaches.