Project 2

PROJECT SUMMARY / ABSTRACT Hyperphosphorylated tau is the primary component of neurofibrillary tangles (NFTs), a pathological hallmark of several neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Since accumulation of hyperphosphorylated tau (p-tau) correlates with the onset of cognitive symptoms, we aim to evaluate and validate inhibition of cytosolic histone deacetylase 6 (HDAC6), which modulates the accumulation of hyperphosphorylated tau, as a lead strategy for the treatment of Alzheimer's disease (AD) and related neurodegenerative tauopathies. We seek to target HDAC6, through the use of a novel blood-brain-barrier-permeable inhibitor, as a means to delay emergence of tau pathology. We have already identified HDAC6 as a highly drug-able target and present new evidence that inhibiting HDAC6 leads to hyperacetylation and enhanced degradation of tau. We propose that acetylation of tau within KXGS motif regions (detectable with our novel site-specific antibody ac-KIGS), which are critical for tau to bind microtubules, counter balances phosphorylation on this same motif (recognized by 12E8). Given that tau species phosphorylated on KXGS motifs accumulate in neurofibrillary tangles, fail to bind and stabilize microtubules, and are not recognized by cellular degradation machinery, we hypothesize that loss of HDAC6 activity will increase the ratio of acetylation to phosphorylation on KXGS motifs to favor tau clearance, thereby preventing neuropathology and disease progression. There are no obvious, known counter indications regarding HDAC6 inhibition: HDAC6 knockout mice exhibit no overt deleterious phenotypes; we have not observed obvious toxicity with our lead HDAC6 inhibitors in cells or in mice; and selective inhibition of HDAC6 versus other HDAC isoforms has been shown to preserve normal gene expression in cells, thereby minimizing toxicity to patients. As such, we envision the use of HDAC6 modulation, in concert with the advent of techniques designed to detect and image amyloid beta peptide (Ab) pathology years to decades before the onset of cognitive symptoms, as a means to interrupt the development and progression of p-tau accumulation initially triggered by Ab deposition. In so doing, we aim to provide a greater understanding of the value of HDAC6 inhibition in slowing the onset or progression of tauopathies and, upon completion, will deliver a very compelling data package to warrant further clinical development of this novel therapeutic strategy for AD and other tauopathies.