USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
Tesi di Dottorato
Data di Pubblicazione:
2019
Citazione:
USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE / S. Therin ; tutor: M. Di Luca ; co-tutor: E. Marcello ; coordinator: A. L. Catapano. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2019 Jun 24. 31. ciclo, Anno Accademico 2018. [10.13130/therin-sebastien_phd2019-06-24].
Abstract:
Alzheimer’s disease (AD) is characterized by the aggregation of amyloid beta peptide (Aβ). Aβ derives from the amyloid precursor protein (APP), which can undergo two mutually exclusive pathways. The amyloidogenic pathway involves BACE and γ-secretase activities and leads to Aβ formation. While, the non-amyloidogenic pathway involves ADAM10, a disintegrin and metalloproteinase 10, which cleaves APP within the domain corresponding to Aβ, thus precluding Aβ production. Recently, we identified a new ADAM10 binding partner, named AP2, which is responsible for ADAM10 internalization, therefore affecting its activity. Interestingly, ADAM10/AP2 interaction is significantly increased in AD patients' brain compared to healthy control subjects, suggesting a role of ADAM10/AP2 in AD pathogenesis. In this framework, we have recently developed a cell permeable peptide (named PEP3) capable of interfering with ADAM10/AP2 association. The intraperitoneal administration of this CPP to a mouse model of AD for two weeks is safe and effective in impairing ADAM10 endocytosis and, thereby, in increasing ADAM10 synaptic localization. At late stages of disease, the PEP3 administration is able to change biochemical parameters, as Aβ levels and the molecular composition of the synapses without ameliorating the cognitive deficits of these mice. On the other hand, at early stage of the pathology the 14-days administration of the PEP3 rescues the cognitive impairment of the AD mice. Further investigations revealed that the synaptic levels of the NMDA receptor subunit GluN2A are increased upon the treatment and that previously observed shrinkage and dendritic spine loss in AD mice were improved after CPP treatment. These results are mediated by an increase in endogenous sAPPα. These positive results point to ADAM10 internalization as a potential target mechanism for the development of an effective AD therapy.
Tipologia IRIS:
Tesi di dottorato
Keywords:
Alzheimer's disease; ADAM10; Amyloid precursor protein; Amyloid beta; APP/PS1 mouse
Elenco autori:
S. Therin
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