Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease

Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer's disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD.