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Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model

Lin, Fangjua; Jia, Jianpinga,b,c,d; Qin, Weia,b,c,d

doi: 10.1097/WNR.0000000000000261
Degeneration and Repair

The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer’s disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling and the Aβ oligomer are lacking, and the mechanisms underlying the effect of central insulin signaling on AD are still elusive. Our team has established the Presenilin-1 Val97Leu mutant transgenic (PS1V97L) AD mouse model with the intraneuronal Aβ oligomer as the potential initiator for other pathologies, but without extracellular amyloid plaque formation. Using this model, we investigated the roles of disturbed central insulin signaling induced by intracerebroventricular injection of streptozotocin (STZ) in the progression of AD. We observed that PS1V97L mice after intracerebroventricular injection of STZ showed increased Aβ oligomer accumulation and aggravated spatial learning and memory deficit in the absence of diabetes symptoms. Furthermore, STZ administration inhibited the activation of the insulin receptor and enhanced the activation of c-Jun NH2-terminal kinase, which was accompanied by increased production of carboxy-terminal fragments from the amyloid precursor protein, in the brain of PS1V97L mice. Overall, our study provided in-vivo evidence for a role of central insulin signaling in AD progression.

aDepartment of Neurology, Xuan Wu Hospital, Capital Medical University

bCenter of Alzheimer’s Disease, Beijing Institute for Brain Disorders

cBeijing Key Laboratory of Geriatric Cognitive Disorders

dKey Neurodegenerative Laboratory of Ministry of Education of the People’s Republic of China, Beijing, China

Correspondence to Jianping Jia, PhD, MD, Xuan Wu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China Tel: +86 10 83198899; fax: +86 10 83171070; e-mail: jiaxuanwu@126.com

Received July 14, 2014

Accepted August 15, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins