Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Abstract

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Moreover, restoring brain levels of CBP, while improving memory function, did not modify Aβ levels, plaques, or Tau immunoreactivity in a model exhibiting both amyloid plaques and neurofibrillary tangles [156]. Restoring memory functions with the HDAC inhibitor 4-phenylbutyrate increased dendritic spine density in CA1 and the clearance of intraneuronal Aβ accumulation [159,160], even when a similar treatment did not affect Aβ levels and plaques [161]. Further, HDAC inhibition promotes decreased tau phosphorylation through, at least, downregulating GSK3β activity [161].…”

“…Restoring memory functions with the HDAC inhibitor 4-phenylbutyrate increased dendritic spine density in CA1 and the clearance of intraneuronal Aβ accumulation [159,160], even when a similar treatment did not affect Aβ levels and plaques [161]. Further, HDAC inhibition promotes decreased tau phosphorylation through, at least, downregulating GSK3β activity [161]. Nonetheless, the inhibition of p300 and likely CBP has been associated with decreased Tau acetylation and the elimination of hyperphosphorylated Tau species [162].…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…As a therapeutic strategy to increase acetylation, the inhibition of HDACs by compounds such as phenyl butyrate, trichostatin A or Suberoylanilide hydroxamic acid (SAHA) is protective in cellular and animal models of both AD and HD 69,126,127 (Suppl Table S3). HDAC inhibitors such as SAHA (Vorinostat, Merck) or valproic acid are currently undergoing Phase II/III clinical trials for different types of cancer, which together with the high degree of target validation for HDACs makes them good candidates for clinical trials in neurodegenerative disease.…”

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Histone modifications proposed to regulate sexual differentiation of brain and behavior

“…Chromatin remodeling has also been implicated in the development of pathological conditions such as depression and addiction [93,94] and has been shown to be induced by acute and chronic stress [95]. Furthermore, epigenetic dysregulation, specifically reduced histone acetylation, is a common theme in neurodegenerative and neurodevelopmental disorders [96,97]. Based on these evidence, histone deacetylase (HDAC) inhibitors are now considered as valid drug targets for the treatment of a number of neurological and psychiatric disorders [96].…”