Small Molecule Activators of PP2A Suggests Controlled Tau
Phosphorylation as a Novel Mode of therapy for Alzheimer's disease
Abstract
Alzheimer’s disease (AD) is characterized by neurofibrillary tangles
(NFTs), formed as a consequence of hyperphosphorylation of tau. The
extent of phosphorylation of tau is regulated by protein phosphatases
(PPs) like PP1, PP2A/Bα, PP2B and PP5. Interestingly, PP2A/Bα, is a
major brain tau phosphatase which account for 70% of the
dephosphorylation events in brain and, its activity is known to decrease
by half under AD conditions. The down regulation of PP2A leads to
hyperphosphorylation of Tau in the brains of AD patients. Hence, the
process of reversal of tau phosphorylation needs to be achieved by the
activation of PP2A, through specific molecules, as this could pave way
towards development of novel therapeutics for AD. The key objective of
the current study was thus to understand the affinities of various small
molecules that could function as potential activators of PP2A. Molecules
like Xylulose-5-Phosphate, Dihydroxy Phenylethanol, EGCG, Memantine,
Sodium Selenate, Tetralone and Quinolone exhibit strong interactions
across identified binding pockets of PP2A. The investigation not only
confers that there could be more than one activation site in PP2A, but
also offers clues as to how these molecules facilitate restoration of
the phosphatases activity, thus proposing newer avenues for the
treatment of AD.