Calpastatin Mediates Development of Alzheimer’s Disease in Diabetes

Article type: Research Article

Authors: Zhu, Lingyan^{a; b} | Gong, Li^a | Yang, Tianlun^{a; *} | Xiao, Xiangwei^{c; *}

Affiliations: [a] Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China | [b] Department of Endocrinology, The First Affiliated Hospital of NanChang University, Nanchang, China | [c] Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Xiangwei Xiao, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Ave, Pittsburgh, PA15224, USA. Tel.: +14126929210; Fax: +14126923466; E-mail: [email protected] and Tianlun Yang, Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410078, China. Tel.: +8613707315500; E-mail: [email protected].

Abstract:  Aged people have a high chance to develop two prevalent diseases, diabetes and Alzheimer’s disease (AD), which are characterized with hyperglycemia and neurodegeneration, respectively. Interestingly, recent evidence suggest that diabetes is a predisposing factor for AD. Nevertheless, the mechanisms underlying the association of diabetes with AD remain poorly defined. Here, we studied the effects of diabetes on AD in mice. The APP-PS1 mouse, an AD-prone strain, was administrated with streptozotocin (STZ) to destroy 75% beta cell mass to induce sustained hyperglycemia. We found that STZ-treated APP-PS1 mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to saline-treated normoglycemic APP-PS1 mice, likely resulting from increases in brain deposition of amyloid-β peptide aggregates (Aβ). Since formation of Aβ is known to be induced by protein hyperphosphorylation mediated by calpain (CAPN)-induced cleavage of p35 into p25, we examined levels of these proteins in mouse brain. We detected not only increased p35-to-p25 conversion, but also enhanced CAPN1 activity via increased protein but not mRNA levels. The internal CAPN1 inhibitor, calpastatin (CAST), was downregulated in STZ-treated APP-PS1 mouse brain, as a basis for the increase in CAPN1. In vitro, a human neuronal cell line, HCN-2, increased CAPN1 activity and downregulated CAST levels when incubated for 8 days in high glucose level, resulting in increased cell apoptosis. Together, these data suggest that chronic hyperglycemia may promote AD development through downregulating CAST.

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, calpain 1, calpastatin, diabetes

DOI: 10.3233/JAD-190004

Journal: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1051-1059, 2019