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

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by tau and alpha-synuclein protein inclusions, respectively.
• Histone deacetylase 6 (HDAC6) is implicated in the regulation of protein aggregation.
• Current treatments for AD and PD lack efficacy in targeting the underlying protein pathologies.

Purpose of the Study:

• To investigate the therapeutic potential of HDAC6 inhibitors in reducing tau and alpha-synuclein pathologies.
• To evaluate the efficacy of a specific HDAC6 inhibitor, ACY-738, in preclinical models of AD and PD.

Main Methods:

• Primary rat cortical neurons were treated with tau and alpha-synuclein fibrils to induce protein inclusions.
• HDAC6 expression was knocked down using shRNA delivered via AAV.
• Wild-type mice received intracerebral injections of tau and alpha-synuclein fibrils, followed by oral administration of ACY-738.
• Immunohistochemistry was used to quantify tau and alpha-synuclein pathology in treated animals.

Main Results:

• HDAC6 inhibitors and shRNA-mediated knockdown reduced tau and alpha-synuclein inclusions in primary neurons.
• Oral administration of ACY-738 effectively inhibited brain HDAC6 activity in mice.
• ACY-738 treatment significantly reduced tau pathology in mice under both pre- and post-seeding dosing schemes.
• Pre-seeding ACY-738 administration significantly reduced alpha-synuclein pathology, with a trend observed for post-seeding administration.

Conclusions:

• HDAC6 inhibition is a promising therapeutic strategy for neurodegenerative diseases characterized by tau and alpha-synuclein aggregation.
• ACY-738 demonstrates significant potential for treating Alzheimer's disease, Parkinson's disease, and related disorders.