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Deficiency in a fly ortholog of HS‐aging related gene, sulfonylurea receptor/ SUR , increased vulnerability to neurodegeneration in drosophila models of Alzheimer’s disease
Author(s) -
Sekiya Michiko,
Quan Xiuming,
Sakakibara Yasufumi,
Chikamatsu Sachie,
Iijima Koichi M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042787
Subject(s) - neurodegeneration , biology , neuroprotection , genetics , neuroscience , medicine , disease
Background Hippocampal sclerosis of aging (HS‐aging) is a common senile dementia characterized by sever neuron loss and gliosis in the hippocampus, and clinically mimics Alzheimer’s disease (AD). Polymorphisms in GRN , TMEM106B and ABCC9 have previously shown the association with HS‐Aging. However, the mechanisms and a molecular link between HS‐aging and AD remain elusive. Sulfonylurea receptors (SURs: ABCC8/SUR1 and ABCC9/SUR2) are the regulatory subunits of ATP‐sensitive potassium channels that coordinate energetic status and intracellular Ca 2 + levels in various cells. Mutations in SURs causes diabetes and cardiovascular diseases, both of which are known AD risks. Interestingly, single nucleotide polymorphism that increases the mRNA levels of ABCC9/SUR2 has been associated with a risk for HS‐aging, suggesting that ABCC9/SUR2 might influence pathogenesis of AD as well as HS‐aging. Method Using Drosophila as a model, we asked whether deficiency in Sur , a fly ortholog of SURs, is protective or detrimental to neuronal integrity during aging and under neurodegenerative conditions. Result We found that Sur deficiency by itself did not affect age‐associated changes in neuronal function and integrity. In contrast, Sur deficiency significantly worsened behavioral deficits and neurodegeneration by impairing energy metabolism in a fly model of amyloid‐β42 toxicity. We also demonstrated that Sur deficiency significantly exacerbated tau‐mediated neurodegeneration and AD‐related tau phosphorylation. Conclusion This study suggests that ABCC9/SUR2 plays neuroprotective roles in the pathogenesis of AD and that increased ABCC9/SUR2 might extend clinical onset of AD.