Histone Deacetylation in Alzheimer’s Diseases (AD); Hope or Hype
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Date
2025-01-18
Journal Title
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Cell Biochemistry and Biophysics/ springer
Abstract
Abstract
Histone acetylation is the process by which histone acetyltransferases (HATs) add an acetyl group to the N-terminal lysine
residues of histones, resulting in a more open chromatin structure. Histone acetylation tends to increase gene expression
more than methylation does. In the central nervous system (CNS), histone acetylation is essential for controlling the
expression of genes linked to cognition and learning. Histone deacetylases (HDACs), “writing” enzymes (HATs), and
“reading” enzymes with bromodomains that identify and localize to acetylated lysine residues are responsible for
maintaining histone acetylation. By giving animals HDAC inhibitors (HDACis), it is possible to intentionally control the
ratios of “writer” and “eraser” activity, which will change the acetylation of histones. In addition to making the chromatin
more accessible, these histone acetylation alterations re-allocate the targeting of “readers,” including the transcriptional coactivators, cAMP response element-binding protein (CBP), and bromodomain-containing protein 4 (Brd4) in the CNS.
Conclusive evidence has shown that HDACs slow down the progression of Alzheimer’s disease (AD) by reducing the
amount of histone acetylation, decreasing the activity of genes linked to memory, supporting cognitive decline and Amyloid
beta (Aβ) protein accumulation, influencing aberrant tau phosphorylation, and promoting the emergence of neurofibrillary
tangles (NFTs). In this review, we have covered the therapeutic targets and functions of HDACs that might be useful in
Treating AD.
Description
Overview of Histone Acetylation:
Histone acetylation is a biochemical process in which histone acetyltransferases (HATs) add acetyl groups to specific lysine residues on histone proteins.
This modification results in a more open chromatin structure, which allows for increased gene expression.
Compared to methylation, acetylation more strongly enhances gene activity.
Role in the Central Nervous System (CNS):
In the CNS, histone acetylation is crucial for regulating genes involved in cognition and learning.
Proper acetylation levels help maintain brain functions related to memory and information processing.
Key Enzymes Involved:
HATs (Writers): Add acetyl groups to histones.
HDACs (Erasers): Remove acetyl groups, leading to tighter DNA packaging and reduced gene activity.
Bromodomain proteins (Readers): Recognize acetylated histones and help regulate gene expression by interacting with other proteins like CBP and Brd4.
Therapeutic Modulation Using HDAC Inhibitors:
HDAC inhibitors (HDACis) block HDAC activity, increasing histone acetylation.
This shift enhances gene expression by making chromatin more accessible and altering the activity of reader proteins.
Connection to Alzheimer’s Disease (AD):
HDACs are implicated in worsening AD by:
Decreasing histone acetylation.
Suppressing memory-related genes.
Increasing amyloid-beta (Aβ) buildup.
Promoting abnormal tau phosphorylation and the formation of neurofibrillary tangles (NFTs).
Research supports targeting HDACs as a potential treatment for AD, aiming to reverse or slow cognitive decline.
Conclusion:
The abstract reviews the biological roles and therapeutic potential of HDACs in treating Alzheimer’s disease, focusing on how modifying histone acetylation affects gene regulation in the brain.
Keywords
Citation
Ateya, N. H., Al-Taie, S. F., Jasim, S. A., Uthirapathy, S., Chaudhary, K., Rani, P., ... & Ahmed, J. K. (2025). Histone Deacetylation in Alzheimer’s Diseases (AD); Hope or Hype. Cell Biochemistry and Biophysics, 1-17.