CALHM2 V136G polymorphism reduces astrocytic ATP release and is associated with depressive symptoms and Alzheimer's disease risk
Yang Liao, Yingyi Wang, Qing‐Qing Tao, Chaoguang Yang, Jinlei Wang, Jinbo Cheng, Jun Ma, Zhi‐Ying Wu, Rui‐Yuan Pan, Zengqiang Yuan- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
INTRODUCTION
Depression is considered a prodromal state of Alzheimer's disease (AD), yet the underlying mechanism(s) by which depression increases the risk of AD are not known.
METHODS
Single‐nucleotide polymorphism (SNP) analysis was used to determine the CALHM2 variants in AD patients. Cellular and molecular experiments were conducted to investigate the function of CALHM2 V136G mutation. We generated a new genetically engineered Calhm2 V136G mouse model and performed behavioral tests with these mice.
RESULTS
CALHM2 V136G mutation (rs232660) is significantly associated with AD. V136G mutation resulted in loss of the CALHM2 ATP‐release function in astrocytes and impaired synaptic plasticity. Mice homozygous for the Calhm2 V136G allele displayed depressive‐like behaviors that were rescued by administration of exogenous ATP. Moreover, Calhm2 V136G mutation predisposed mice to cognitive decline in old age.
DISCUSSION
CALHM2 dysfunction is a biologically relevant mechanism that may contribute to the observed clinical correlation between depression and AD.