Stage‐dependent involvement of ADAM10 and its significance in epileptic seizures

Abstract

The prevalence of epileptic seizures in Alzheimer's disease (AD) has attracted an increasing amount of attention in recent years, and many cohort studies have found several risk factors associated with the genesis of seizures in AD. Among these factors, young age and severe dementia are seemingly contradictory and independent risk factors, indicating that the pathogenesis of epileptic seizures is, to a certain extent, stage‐dependent. A disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) is a crucial α‐secretase responsible for ectodomain shedding of its substrates; thus, the function of this protein depends on the biological effects of its substrates. Intriguingly, transgenic models have demonstrated ADAM10 to be associated with epilepsy. Based on the biological effects of its substrates, the potential pathogenic roles of ADAM10 in epileptic seizures can be classified into amyloidogenic processes in the ageing stage and cortical dysplasia in the developmental stage. Therefore, ADAM10 is reviewed here as a stage‐dependent modulator in the pathogenesis of epilepsy. Current data regarding ADAM10 in epileptic seizures were collected and reviewed for potential pathogenic roles (ie amyloidogenic processes and cortical dysplasia) and regulatory mechanisms (ie transcriptional and posttranscriptional regulation). These findings are then discussed in terms of the significance of the stage‐dependent functions of ADAM10 in epilepsy. Several potential targets for seizure control, such as candidate transcription factors and microRNAs that regulate ADAM10, as well as potential genetic screening tools for the early recognition of cortical dysplasia, have been suggested but must be studied in more detail.

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

“…In this manner, ADAM10 may actually be protective in AD and prevent the formation of senile plaques. Interestingly, ADAM10 has been implicated in the pathogenesis of focal cortical dysplasia [ 84 , 85 ], a disease characterized by epileptic seizures and neurocognitive deficit. Overexpression of ADAM10 in a mouse temporal lobe epilepsy model also attenuates the burden of seizures and prevents pathological neuroinflammation [ 86 ].…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…Potential pathogenic genes for epilepsy include ion channel genes (e.g., SCN1A, KCNQ2, SCN2A, and SCN8A), which account for nearly half of epilepsy genes, together with a number of additional genes, such as CDKL5, STXBP1, PCDH19, PRRT2, LGI1, ALDH7A1, MECP2, EPM2A, ARX, and SLC2A1 [267]. There is also an association of MTHFR rs1801133 and ABCC2 rs717620 with susceptibility to generalized tonic-clonic epilepsy, while ABCB1 rs717620 is associated with poor response to antiepileptics [268].…”

Select Macrophage Noncoding RNAs of Interest in Cardiovascular Disease

“… 26 In THP1 macrophage-derived foam cell lines, ANRIL suppressed atherosclerotic-like inflammatory responses and promoted cholesterol efflux. 34 ANRIL was shown to regulate ADAM10, a disintegrin and metalloproteinase domain-containing protein, that has been shown to be involved in neuroinflammation 35 and expressed at high levels in atherosclerosis. 36 The overexpression of ANRIL was found to result in methylation of the ADAM10 gene, which has been shown to inhibit atherosclerotic inflammation.…”