Abstract
Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD) mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG). We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP) level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders characterized by progressive cognitive decline and memory impairment
Consistent with the previous study (Saura et al, 2004), we found that conditional double knockout (cDKO) mice showed only contextual fear memory impairment in a 24-h retention test at 5-month-old age
We evaluated whether histone deacetylase (HDAC) inhibitors have beneficial effects on PS cDKO mice—an Aβ-independent mouse model of AD-like phenotypes but with no amyloid deposition
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders characterized by progressive cognitive decline and memory impairment. It is defined by the presence of neurofibrillary tangles (NFTs) and senile plaques in the brain, composed of hyperphosphorylated tau and extracellular insoluble β-Amyloid (Aβ), respectively (Selkoe, 2001). The malfunction of Presenilins causes amyloid to accumulate into plaques in the brain (De Strooper et al, 1998). It is worth noting that memory deficits and neurodegeneration in cDKO mice are not caused by Aβ accumulation as PS deletion reduced Aβ production (Beglopoulos et al, 2004), which is inconsistent with the Aβ hypothesis of the pathogenesis of AD.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
