Abstract
Evidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer’s disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.
Highlights
Alzheimer’s disease (AD) is the most common neurogenerative disorder leading to dementia [3]
Our results show that Retinoblastoma-Binding Protein 7 (Rbbp7) is downregulated in postmortem brain tissue, the middle temporal gyrus (MTG), of AD patients and is negatively associated with CERAD neuritic plaque density and Braak stage, but not with Lewy body stage
We identify a reduction of Rbbp7 in PS19 mice that precedes tau pathology and decreases significantly with age
Summary
Alzheimer’s disease (AD) is the most common neurogenerative disorder leading to dementia [3]. In tauopathies like AD, Frontotemporal dementia, Corticobasal degeneration, and Pick’s disease, tau is hyper-phosphorylated, reducing its binding affinity to microtubules and resulting in accumulation into insoluble intra-neuronal tau filaments [20, 21, 28]. Braak Staging, a well-established method that scores the accumulation of phospho-tau, is based on AT8 antibody staining [11, 12] These findings are consistent with work in mouse models with human tau mutations [1]. The PS19 mouse model, which harbors the mutant human tau gene (TauP301S) that causes familial frontotemporal dementia [52], shows significant neuronal loss and a prominent AT8 staining compared to other tau phosphorylation epitopes [1, 52]. While there is ample evidence that tau hyper-phosphorylation leads to neurofibrillary tangle (NFT) development and neuronal loss, the complete mechanisms underlying tau pathogenesis remain largely elusive [18, 26, 27, 30, 56]
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