Knockdown Of Pp32Reverses P300/CBP Histone Acetylase Activity And Ameliorates Cognitive Deficits

[Background]Long-lasting forms of memories require stable gene expression changes, which are in part orchestrated by chromatin templated epigenetic processes. Of the epigenetic modifications identified so far in the nervous system, histone acetylation has been unequivocally associated with facilitating learning and memory. Acetylation diminishes the electrostatic affinity between neighbouring histones and the DNA and, consequently, can promote a more open chromatin structure that allows for memory-related gene transcription. Accordingly, pharmacological treatments aimed at increasing histone acetylation have shown promising results in reversing cognitive deficits in some of these models, predominantly by the use of non-selective HDAC (histone deacetylase) inhibitors. However, the causative agent of such memory-impairing histone acetylation changes, and the best targets for pharmacological strategies, remain unknown.To date, only three HATs have been implicated in the molecular mechanisms underlying memory formation:CBP, p300and PCAF. It was demonstrated that the CBP HAT domain is necessary for memory storage, including spatial memory, a hippocampus dependent form of memory. And the loss in acetyltransferase activity has been causally linked to several neurodegenerative disorders. Altogether, these studies represent evidence that a therapeutic strategy specifically targeted to CBP HAT activation could be suitable in several neurodegenerative disease. One likely candidate is pp32, a key Subunit of the INHAT negatively regulates p300/CBP HAT (histone acetylase). Histone binding specificity of pp32is a prerequisite for HAT inhibition. pp32, as an endogenously produced inhibitory protein of PP2A, is selectively up-regulated in the areas of AD brain affected with neurofibrillary pathology. [Objective]To investigate the mechanisms that knockdown of pp32attenuates cognitive deficits in two mouse models of neurodegeneration.[Methods]Construct Lentiviral of siRNA targeting pp32(Lenti-NC, Lenti-Sipp32). The memory dificits aged mice were selected by Morris water maze for6days. Memory deficits aged mice and h-tau transgenic mice were injected2μl of Lenti-NC-RFP or Lenti-sipp32-RFP into the hippocampal CA3with a stereotaxic instrument.1month later, cognitive abilities were measured by Morris water maze test and step down test. Immunohistochemistry, western blot, reverse transcription PCR and protein phosphatas activity assay were used to detect synaptic relative proteins, tau and PP2A activity. Golgi staining was used to analyse dendritic morphology and spine density in hippocampal CA3neurons.[Results]Sipp32decreased the mRNA and expression of pp32in memory deficits aged mice and h-tau transgene mice. Down-regulation of pp32attenuates the cognitive abnormality and increases the complexity of dendritic arbors, spine density and synaptic protein in two kinds of memory-deficits mice. In addition, the mRNA of synaptic protein was increased and the tau hyperphosphorylation was decreased.[Conclusions]Knockdown of pp32ameliorated memory deficits by reversing HAT actvity.