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.
We aim to evaluate and validate inhibition of cytosolic histone deacetylase 6 (HDAC6), an enzyme that modulates the balance between acetylation and hyperphosphorylation of the protein tau, as a lead strategy for the treatment of Alzheimer's disease and related tauopathies. Since accumulation of hyperphosphorylated tau correlates with the onset of cognitive symptoms, we seek to inhibit HDAC6 as a means to delay disease onset or progression. We are developing cell and transgenic mouse models to test whether modulation of HDAC6 protects neurons by increasing degradation, or removal, of the toxic phosphorylated protein and simultaneously decreasing tau's propensity to aggregate.
|Kertesz, A; Finger, E; Murrell, J et al. (2015) Progressive supranuclear palsy in a family with TDP-43 pathology. Neurocase 21:178-84|
|Zhang, Bing; Ferman, Tanis J; Boeve, Bradley F et al. (2015) MRS in mild cognitive impairment: early differentiation of dementia with Lewy bodies and Alzheimer's disease. J Neuroimaging 25:269-74|
|Nedelska, Zuzana; Ferman, Tanis J; Boeve, Bradley F et al. (2015) Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies. Neurobiol Aging 36:452-61|
|Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E et al. (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. Brain 137:1533-49|
|Steffen, Teresa M; Boeve, Bradley F; Petersen, Cheryl M et al. (2014) Long-term exercise training for an individual with mixed corticobasal degeneration and progressive supranuclear palsy features: 10-year case report follow-up. Phys Ther 94:289-96|
|Cannon, Ashley; Bieniek, Kevin F; Lin, Wen-Lang et al. (2014) Concurrent variably protease-sensitive prionopathy and amyotrophic lateral sclerosis. Acta Neuropathol 128:313-5|
|van Blitterswijk, Marka; Mullen, Bianca; Wojtas, Aleksandra et al. (2014) Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. Mol Neurodegener 9:38|
|Graff-Radford, Jonathan; Murray, Melissa E; Lowe, Val J et al. (2014) Dementia with Lewy bodies: basis of cingulate island sign. Neurology 83:801-9|
|Mielke, Michelle M; Weigand, Stephen D; Wiste, Heather J et al. (2014) Independent comparison of CogState computerized testing and a standard cognitive battery with neuroimaging. Alzheimers Dement 10:779-89|
|Pedraza, Otto; Allen, Mariet; Jennette, Kyle et al. (2014) Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects. Alzheimers Dement 10:205-13|
Showing the most recent 10 out of 556 publications