Effetto del peptide Tat-BH4 sulla produzione di FGF2 in cellule endoteliali esposte a beta-amiloide

One of the basic events for the development of serious neurodegenerative diseases such as Alzheimer Disease (AD) and Cerebral amyloid angiopathie (CAA) is accumulation of the β-amyloid peptide on the cerebral vasculature. It is known that behind the several existing clinical conditions for these pathologies there are mutant forms of the peptide, as the E22Q (also known as the "Dutch" variant), the more toxic. The overall toxicity is exerted partially through the induction of oxidative stress and the impairment in the production of trophic factors, like fibroblast growth factor-2 (FGF-2). As a consequence, cells undergo apoptosis and the whole neurovascular system gets damaged. Right now, the need for specific dugs targeting the beta-amyloid pathway is strong, and the present therapies aim at reducing the simptoms through acetilcholinesterase inhibitors and glutamatergic modulators. As a recent effort, Tat-BH4, initially developed for the treatment of ischeamia, is being investigated for its potential in reversing the apoptotic component in these diseases.
This peptide was built joining together the membreane permeant domain of the HIV protein Tat, as a carrier, and the anti-apoptotic domain of Bcl-2 (an important endogenous mediator of cell survival). As a matter of fact, the treatment of endothelial cells with this contruct has been demonstated to protect the cells from the β-amyloid induced damage. This protective effect is exerted via activation of the Akt/Nitric Oxide Sinthase (eNOS) pathways and, given the overlap of the relative signaling cascades with that of the essential factor FGF-2, we investigated if the trophic recovery was somehow due to an overproduction of this protein.