Abstract
Alzheimer’s disease has been shown to have a global reduction in gene expression, called an epigenetic blockade, which may be regulated by histone post-translational modifications. Histone H3 has been shown to be highly regulated by phosphorylation. We, therefore, chose H3 for investigation of phosphorylation of the core sites serine-57 (S57) and threonine-58 (T58). Hemispheres of brains from a mouse model of rapid amyloid deposition (5XFAD) were used for measurement of S57 and T58 phosphorylation. Multiple reaction monitoring (MRM) was used to measure the level of phosphorylation, which was normalized to a non-modified “housekeeping” peptide of H3. S57 phosphorylation was decreased by 40%, T58 phosphorylation was decreased by 45%, and doubly phosphorylated S57pT58p was decreased by 30% in 5XFAD brain in comparison to C57BL/6J age- and sex-matched wild type controls. Amyloid-β (Aβ) and amyloid precursor protein were also measured to confirm that 5XFAD mice produced high levels of Aβ. Decreased phosphorylation of these sites in close proximity to DNA may lead to stabilization of DNA–histone interactions and a condensed chromatin state, consistent with the epigenetic blockade associated with AD. Our findings of H3 sites S57 and T58 exhibiting lower levels of phosphorylation in 5XFAD model compared to wild type control implicate these sites in the epigenetic blockade in neurodegeneration pathology.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the sixth leading cause of death in the U.S [1]
post-translational modification (PTM) are largely found on the N-terminal domains, commonly referred to as tail regions, that extend from the histone core complex
Our study shows that phosphorylation of both S57 and T58 on histone H3 is lower in 5XFAD models of amyloid deposition in comparison to wild type controls
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the sixth leading cause of death in the U.S [1]. One common PTM on histones is phosphorylation of serine (Sp) and threonine (Tp) residues, which has been linked to activation and repression of genes based on site of modification and condition of cells [7,8,9]. To mimic the amyloid pathology found in humans with AD, transgenic mice with genetic mutations that cause rapid amyloid deposition have been created as models of AD pathology [20] One of these models, called 5XFAD mice, overexpress two human proteins with five mutations of familial AD: PS1 with M146L and L286V and APP695 with Swedish (K670N, M671L), Florida (I176V), and London (V717I) mutations. Our study shows that phosphorylation of both S57 and T58 on histone H3 is lower in 5XFAD models of amyloid deposition in comparison to wild type controls. Since changes in PTMs of histones are established to influence genetic expression, our measurements of specific histone H3 residues S57 and T58 may provide insight into the epigenetic blockade phenomenon in the pathology of neurodegeneration
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