HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice

Abstract

A previous compound screen identified two molecules with histone deacetylase 6 (HDAC6) inhibitory activity that reduced Alzheimer's disease (AD)-like tau inclusions in a primary rat cortical neuron model seeded with AD brain-derived tau fibrils. Testing here of additional HDAC6-selective inhibitors confirmed that compounds of this type decreased neuronal tau inclusions. Moreover, HDAC6 inhibitors also reduced Parkinson's disease (PD)-like α-synuclein aggregates in primary neurons seeded with recombinant α-synuclein fibrils. Knockdown of HDAC6 expression through treatment of seeded neuron cultures with AAV harboring HDAC6-specific shRNA also resulted in a reduction of tau and α-synuclein inclusions. Multiple compounds were evaluated for their ability to inhibit brain HDAC6 in mice, and ACY-738 was found to effectively inhibit brain HDAC6 activity upon oral dosing. ACY-738 was utilized in an efficacy study in which tau and α-synuclein pathologies were induced in wild-type mice through intracerebral injections of AD brain-derived tau and α-synuclein fibrils. Groups of male and female mice first received ACY-738 in drinking water 1 d prior to (preseeding) or 1 week after (postseeding) brain injections of fibrils, followed by continued dosing for an additional 3 months. A control group of fibril-injected mice received water without ACY-738. Immunohistochemical evaluations revealed that ACY-738 administration resulted in significant reductions of tau pathology in both dosing schemes. Moreover, α-synuclein pathology was significantly reduced in mice with preseeding ACY-738 administration, with a strong trend toward reduction after postseeding dosing. These results suggest that HDAC6 inhibitors have potential for the treatment of AD, PD, and related diseases.