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CBP and p300 Lead an Epigenetic Response in Alzheimer's Disease-affected Neurons

By Stuart P. Atkinson, Ph.D.

September 4, 2025

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Histone Modification Dysregulation: The Epigenetic Link in Alzheimer's Disease?

Cognitive decline, neurodegeneration, and the accumulation of amyloid-β plaques and tau neurofibrillary tangles in the brain characterize the development of Alzheimer's disease (AD), the most common form of senile dementia (Masters et al.). While we currently lack a complete understanding of the relationships existing between pathological hallmarks and disease features (Busche & Hyman and Bloom), a wealth of studies have suggested that epigenomic dysregulation links aging, disease pathology, and neurodegeneration (Nativio et al., 2018) through the alteration of the transcriptional programs that protect against disease development or worsen disease pathology.

Previous studies from the lab of Shelley L. Berger and others had revealed more abundant levels of acetylated histone H3 lysine 27 (H3K27ac) in the lateral temporal lobe (Creyghton et al.) but lower levels in the entorhinal cortex of AD patient brains (Nativio et al., 2020) when compared to age-matched healthy brain tissue. These findings highlighted the potential complexity and gene specificity when considering the precise occurrence and role of H3K27ac. Unfortunately, the sheer complexity of the human brain and the difficulty in establishing causality in postmortem tissue samples have long represented significant barriers to determining functional relationships between H3K27ac and AD pathology. The definition of any links between histone acetylation and AD development may highlight drugs targeting epigenetic modifiers such as histone acetyltransferases and deacetylases as potential means to overcome what the authors state as a disease-associated "epigenomic blockade" (Gräff et al. and Rodrigues et al.).

In an attempt to avoid these complexity-associated problems, researchers led by Shelley L. Berger (University of Pennsylvania) recently employed a pure population of neurons differentiated from human induced pluripotent stem cells (iPSCs) generated from familial AD patients with an amyloid precursor protein (APP) duplication as a simplified model to study the effects of lowering the levels of the enzymes that catalyze the H3K27ac histone modification – CBP (CREB-binding protein; CREBBP) and p300 (E1A binding protein p300; EP300) (Ogryzko et al. and Raisner et al.). Their exciting new Acta Neuropathologica Communications study now suggests that histone acetylation may drive compensatory gene expression programs in response to AD-associated insults and, as such, may play a crucial role in mitigating AD pathology in neurons (Xu et al.). Overall, this exciting study provides evidence that the CBP/p300 histone acetyltransferases lead an epigenetic response in AD neurons.

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Does Histone Acetylation Mitigate Disease Pathology in Alzheimer's Disease iPSC-derived Neurons?

The histone acetyltransferases p300 and CBP catalyze the formation of H3K27ac, which primarily localizes to enhancer regions and promotes gene transcription; therefore, the authors sought to explore this epigenetic regulatory mechanism in a homogeneous population of relevant neurons and examine its downstream effects on gene expression and AD-related pathology. The induced differentiation of iPSCs via the overexpression of the NGN2 neuronal transcriptional regulator yields an excitatory cortical neuronal cell population with high speed, consistency, and efficiency (Zhang et al.), creating a robust model for investigating neurodegenerative diseases such as AD (Wang et al. and Israel et al.). The authors of this study employed cell samples isolated from familial AD patient donors with an APP duplication and from healthy donors to create iPSC-derived neurons in this manner and subsequently conducted a range of transcriptomic and functional characterization assays.

The knockdown of p300 or CBP via the expression of short interfering RNA (siRNA) resulted in a reduction in total H3K27ac abundance, which correlated with the widespread downregulation of gene transcription in both AD and control neurons (including genes that play important roles in AD). p300 or CBP knockdown resulted in similar transcriptional changes, with learning and memory as well as neuron-related processes being significantly affected. Notably, a subset of APP-amyloid-β pathway genes responsible for amyloid clearance and prevention became strongly upregulated in AD neurons, indicating the activation of a homeostatic genetic response to increased APP abundance and the production of toxic amyloid-β species. The subsequent knockdown of p300 or CBP in AD neurons downregulated the expression of genes with amyloid-reducing function (including the AD-upregulated, compensatory genes) and prompted the increased secretion of toxic amyloid-β species when compared to the same knockdown experiments in control neurons. Notably, CBP knockdown had a more pronounced effect on the amyloid reduction pathways compared to p300 knockdown, which aligns with a previous study from the Berger lab that highlighted the disease-specific activation of CBP but not p300 in postmortem AD brains (Nativio et al., 2020).

Examples of genes impacted by p300/CBP knockdown in AD neurons leading to increased toxic amyloid-β species included the downregulation of LPL (lipoprotein lipase), which normally sequesters amyloid-β (Wang & Eckel), and BDNF (Brain Derived Neurotrophic Factor), which normally reduces amyloid-β production (Matrone et al.). This study also revealed reduced epidermal growth factor receptor (EGFR) expression in AD and control neurons following knockdown of p300 and CBP, with EGFR previously implicated in mediating neurotoxicity downstream of amyloid-β species (Wang et al.). Bioinformatic analyses then suggested that EGFR may represent a central transcriptional mediator of the gene expression alterations observed in response to p300 and CBP knockdown in AD neurons. Overall, this finding suggested the existence of a complex relationship between histone acetylation, gene activation, and the phenotype of amyloid-β species pathology and neurotoxicity.

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Targeting Epigenetic Mechanisms in Neurodegenerative Disorders

Overall, this fascinating study highlights the importance of histone acetylation in driving compensatory gene expression programs in response to neurodegenerative disease that may attempt to mitigate disease pathology in neurons. Indeed, the authors highlight how p300/CBP knockdown in AD neurons reduced H3K27ac levels, inhibited the expression of genetic programs that compensate for increased amyloid-β levels, and consequently prompted increased amyloid-β secretion. These findings suggest targeting histone acetyltransferases as a therapeutic mechanism for neurodegenerative diseases and considering the role of the H3K27ac histone modification as a general activator of transcription that displays cell-type-dependent effects.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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