Abstract
BackgroundReduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer’s disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood.Methods and resultsHere, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca2+ levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aβ. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aβ-induced disruption of ROS, Ca2+ and axonal transport.ConclusionsTaken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aβ. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.
Highlights
Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer’s disease (AD) and is recently being considered a possible therapeutic strategy
Our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well
Prx1 acetylation was decreased in the hippocampus and entorhinal cortex of AD patients compared to age- and sex-matched normal controls
Summary
Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer’s disease (AD) and is recently being considered a possible therapeutic strategy. Aβ disrupts axonal transport by dysregulating microtubule stability and affinity between motor or adaptor proteins and microtubule or cargos [3, 4]. Axonal transport is important for neuronal function and cell viability [5,6,7]. ROS oxidize lipids, proteins and nucleic acids which are essential for normal cellular function, which leads to increased membrane permeability to Ca2+, mitochondrial damage and apoptosis [8,9,10,11]. ROS and Ca2+ damage to mitochondrial axonal transport is mediated by reduced affinity between Miro and kinesin [14, 15]
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