A Comprehensive Analysis of the CaMK2A Gene and Susceptibility to Alzheimer’s Disease in the Han Chinese Population

Abstract

There is ample evidence suggesting that calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) may play an important role in the pathophysiology of Alzheimer’s disease (AD). This genetic study aimed to investigate whether CaMK2A confers susceptibility to the development of AD in the Han Chinese population. A total of seven single nucleotide polymorphisms (SNPs) within CaMK2A were screened in two independent cohorts from southwestern China (333 AD patients and 334 controls) and eastern China (382 AD patients and 426 controls) to discern the potential association between this gene and AD. In addition, a cross-platform normalized expression resource was used to investigate whether CaMK2A is differentially expressed in the brain between individuals with AD and the controls. In addition, expression quantitative trait loci (eQTL) analysis was used to explore the differences in CaMK2A expression in the brain among different genotypes. The cross-platform normalized data showed significant differences in CaMK2A expression in the hippocampus, entorhinal cortex and temporal cortex between the AD patients and the control subjects (|log FC| > 0.1, P < 0.05); however, only the differences in the hippocampus and temporal cortex remained after the multiple comparisons correction [false discovery rate (FDR)-corrected, P < 0.05]. The frequency of the rs4958445 genotype was significantly different between the AD subjects and the controls from southwestern China ( P = 0.013, P = 0.034 after FDR correction). When the two samples were combined, rs4958445 still showed a significant association with AD ( P = 0.044). Haplotype analysis indicated that the T-A-C-A-T-C-C and T-G-C-A-T-C-C haplotypes in the southwestern cohort and the T-G-C-G-C-T-C haplotype in the eastern cohort, consisting of rs10051644, rs6869634, rs3797617, rs3756577, rs4958445, rs10515639 and rs6881743, showed a significant association with AD ( P = 0.037, P = 0.026 and P = 0.045, respectively). Furthermore, the brain eQTL analysis revealed a significant association between the rs4958445 polymorphism and CaMK2A expression in the inferior olivary nucleus ( P = 0.029). Our results suggest an important role for CaMK2A in the pathophysiology of AD in the Han Chinese population, especially the southwestern population.

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer’s Disease

“…Calcium/calmodulin-dependent protein kinase II (Camk2) is a multifunctional protein kinase abundant in the central nervous system (CNS), and it becomes active when it binds to Ca 2+ /calmodulin [ 51 ]. Similar to our results, Fang and colleagues (2019) identified the downregulation of Camk2a in the hippocampus proteome of AD patients, but its expression level was not significantly altered in the pre-frontal cortex [ 52 ]. Another interesting protein in the context of AD is Casein kinase 2, beta polypeptide (Csnk2b).…”

Camk2a suppresses denervated muscle atrophy by maintaining the Ca2+ homeostasis in muscle cells

“…Camk2a is a specific subtype primarily expressed in neural tissues (19)(20)(21). Studies have shown that regulating Camk2a expression in neural tissues, such as the brain and spinal cord, enhances various cognitive abilities and delays the progression of conditions like Alzheimer's disease and depression (22,23). In this study, we found a significant increase in Camk2a expression in denervated muscle tissues, which effectively mitigated Ca 2+ deposition and delayed the progression of muscle atrophy (Figure 3).…”

Epigenetic modifications of DNA and RNA in Alzheimer’s disease

“…Moreover, m6A deposition on 3’UTRs is required for the localization of mRNAs, particularly calcium/calmodulin-dependent protein kinase II (CAMK2) and microtubule-associated protein 2 (MAP2), from the soma to neurites for proper synaptic and growth cone function in hippocampal neurons ( Flamand and Meyer, 2022 ). CAMK2A is a gene known to play roles in synaptic plasticity, memory, and calcium homeostasis, and its dysregulation has been linked to AD susceptibility and pathology ( Ghosh and Giese, 2015 ; Fang et al, 2019 ). MAP2 plays a key role in neurite and synapse growth and function, and its aberrant phosphorylation is associated with neuropsychiatric and neurodegenerative disorders ( Grubisha et al, 2021 ; DeGiosio et al, 2022 ).…”