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P2‐292: Second generation MPAC PBT2 inhibits tau phosphorylation and promotes Aβ degradation
Author(s) -
Barnham Kevin J.,
Crouch Peter J.,
Filiz Gulay,
Cherny Robert A.,
Laughton Katrina,
Volitakis Irene,
Bush Ashley I.,
Masters Colin L.,
Cappai Roberto,
White Anthony R.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1368
Subject(s) - phosphorylation , clioquinol , microbiology and biotechnology , chemistry , kinase , senile plaques , homeostasis , extracellular , biophysics , biochemistry , biology , pharmacology , alzheimer's disease , medicine , disease
Background: The two major pathological lesions associated with Alzheimer’s disease (AD) are the extracellular senile plaques consisting primarily of the amyloidpeptide (A ) and the intracellular neurofibrillary tangles consisting primarily of phosphorylated tau. An ideal therapeutic strategy for AD would be one that targets both of these pathological features. A has been shown to interact with the metal ions Zn and Cu inducing peptide aggregation and the production of toxic reactive oxygen species. Therapeutic strategies for AD based on modulating metal homeostasis using the MPAC clioquinol have shown promising results in both animal and clinical studies. Methods: To further examine the potential of this class of compound we have developed a second generation MPAC (PBT2). This compound is a potent metal ionophore ie it has the ability to transport the metal ions Cu and Zn into the cell, making them bioavailable. In cell culture experiments we have examined the signaling pathways that are activated as a consequence of this ionophoric activity. Results: We have shown that PBT2 is able to alter cell signalling kinases such as PI3K, JNK, ERK1/2. There are a number of downstream actions that occur as a result of these activities; including the dose dependent phosphorylation and therefore inactivation of GSK3 , with the subsequent inhibition of tau phosphorylation. Additionally there is also activation of cell surface metallo-matrix proteinases, in particular MMP2 which degrades secreted monomeric A . Conclusions: These data show the potential benefits of rectifying the errant metallo-homeostasis of AD, removing metals from where they have the potential do harm ie bound to A and shifting these metals to where they can initiate beneficial effects. This ability to target the key proteins associated with both pathological features of AD suggests that PBT2 has the attributes to be an ideal candidate for assessment as a potential therapeutic strategy for AD.