Mapping of Italian research excellence in Neurodegenerative - Apre

progression of the disease.
Aim 2) To study in transgenic mice carrying APP and PS1 mutations the tyrphosphorylation
of APP and CTFs, their interaction with ShcA-Grb2 adaptors and the
influence that such interaction could have on plaque formation, astroglial response,
neuronal death. The use of a Tg model will allow at a deeper comprehension of the
possible correlation between APP phosphorylation, its cleavage, signaling activity and
progressive presence of the typical hallmarks of the disease. Moreover, in this model is
possible also to determine the effect that APP and PS1 mutations, which are linked with a
human familial phenotype, would cause in the above mentioned parameters, and, in a
second step, would allow the application of targeted therapeutical pharmacological
approaches following also the indications raised from the in vitro studies (aim 3).
Aim 3) To study in neuronal and/or glial cell cultures the molecular mechanisms which
regulate APP phosphorylation, influence on cleavage by secretases, coupling with
intracellular adaptors, and signaling activity. Using APP mutants, ShcA mutants, and APP
KO cells we will define the influence that phosphorylation and interaction with ShcA would
cause in signaling activity, cell proliferation and death, and in the generation of
amyloidogenic fragments. Moreover, the study of the effect that proliferative and
apoptotic stimuli may cause on those parameters and/or with the study of the kinases
involved in the activation of APP cleavage and signaling, this would also lead to the
identification of pharmacological target for a therapeutical intervention.