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SGLT2 and DPP4 inhibitors improve Alzheimer's disease–like pathology and cognitive function through distinct mechanisms in a T2D–AD mouse model

 A Young Sim  ;  Da Hyun Choi  ;  Jong Youl Kim  ;  Eun Ran Kim  ;  A-Ra Goh  ;  Yong-Ho Lee  ;  Jong Eun Lee 
 BIOMEDICINE & PHARMACOTHERAPY, Vol.168 : 115755, 2023-12 
Journal Title
Issue Date
Alzheimer Disease* / metabolism ; Amyloid beta-Peptides / metabolism ; Animals ; Body Weight ; Cognition ; Diabetes Mellitus, Type 2* / metabolism ; Dipeptidyl Peptidase 4 / metabolism ; Dipeptidyl-Peptidase IV Inhibitors* / pharmacology ; Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use ; Disease Models, Animal ; Hypoglycemic Agents / pharmacology ; Hypoglycemic Agents / therapeutic use ; Insulin / metabolism ; Insulin Resistance* / physiology ; Mice ; Sodium-Glucose Transporter 2 ; Sodium-Glucose Transporter 2 Inhibitors* / pharmacology ; Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
Alzheimer’s disease ; Amyloid β ; Dipeptidyl peptidase-4 inhibitor ; Hyperphosphorylated tau ; Sodium–glucose cotransporter-2 inhibitor ; Type 2 diabetes mellitus
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium–glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D–AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D–AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D–AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid β (Aβ) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1−7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aβ accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms. © 2023 The Authors
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1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Youl(김종열) ORCID logo https://orcid.org/0000-0002-8340-2894
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
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