☆ 4.7 Article

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

BIOLOGICAL PSYCHIATRY (2022)

Journal

BIOLOGICAL PSYCHIATRY

Volume 91, Issue 4, Pages 389-398

Publisher

ELSEVIER SCIENCE INC

DOI: 10.1016/j.biopsych.2021.01.015

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Abstract

The study found that differential methylation of the CLDN5 gene is associated with changes in cognitive trajectory beyond traditional Alzheimer's disease pathologies. The association between CLDN5 methylation and cognitive decline remains significant even in participants without pathological signs, indicating an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease.

BACKGROUND: Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. METHODS: We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. RESULTS: We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 x 10-7) that was robust to adjustment for cell type proportions (p = 8.52 x 10-7). This association was primarily driven by association with declines in episodic (p = 4.65 x 10-6) and working (p = 2.54 x 10-7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-b and neurofibrillary tangle pathology. CONCLUSIONS: Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer's disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease.

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Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats

Shi-Da Wang, Xue Wang, Yun Zhao, Bing-Hua Xue, Xiao-Tian Wang, Yu-Xin Chen, Zi-Qian Zhang, Ying-Rui Tian, Fang Xie, Ling-Jia Qian

Summary: This study found that chronic stress can lead to cognitive decline, but the specific mechanisms are unclear. Experimental evidence has shown that homocysteine (Hcy) is associated with stress and cognitive decline. Additionally, increased Hcy levels can cause cognitive decline and downregulation of brain-derived neurotrophic factor (BDNF), while reducing Hcy can alleviate these deficits. Furthermore, both stress and Hcy can disrupt DNA methylation in the brain and induce hypermethylation in the BDNF promoter. Interventions with the enzyme ten-eleven translocation (TET1) can alleviate cognitive decline caused by Hcy. These results suggest that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits, and that Hcy-induced DNA hypermethylation in the BDNF promoter may have negative side effects. Additionally, the results suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.

NEUROSCIENCE BULLETIN (2022)