Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction

摘要

Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer’s disease.Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy(DCM), a common cause of heart failure and the most prevalent diagnosis in cardiactransplantation patients. However, the molecular mechanisms, by which presenilin mutations leadto either AD or DCM, are not yet understood. We have employed transgenic Drosophila modelsand optical coherence tomography imaging technology to analyze cardiac function in live adultDrosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reducedheart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast,overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted inirregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrialimpairment. The calcium channel receptor activities in cardiac cells were quantitativelydetermined via real-time RT-PCR. Silencing of dPsn elevated dIP[subscript 3]R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover,overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression ofwingless. Our data provide novel evidence that changes in presenilin level leads to cardiacdysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signalingtransduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.