Amyloid-β and islet amyloid pathologies link Alzheimer's disease and type 2 diabetes in a transgenic model

被引：103

作者：

Wijesekara, Nadeeja ^{[1
]}

Ahrens, Rosemary ^{[1
]}

Sabale, Miheer ^{[3
]}

Wu, Ling ^{[1
]}

Ha, Kathy ^{[1
]}

Verdile, Giuseppe ^{[3
]}

Fraser, Paul E. ^{[1
,2
]}

机构：

[1] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Krembil Discovery Tower,60 Leonard Ave, Toronto, ON M5T 2S8, Canada

[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[3] Curtin Univ, Curtin Hlth & Innovat Res Inst, Sch Biomed Sci, Bentley, WA, Australia

来源：

FASEB JOURNAL | 2017年 / 31卷 / 12期

基金：

英国医学研究理事会;

关键词：

insulin resistance; beta cells; tau; neurodegeneration; hyperglycemia; INSULIN-RESISTANCE; MOUSE MODEL; PLASMA; DYSFUNCTION; IMPAIRMENT; ONSET; INFLAMMATION; MECHANISMS; HYPOTHESIS; DEPOSITION;

D O I：

10.1096/fj.201700431R

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alzheimer's disease (AD) and type 2 diabetes (T2D) present a significant risk to each other. AD and T2D are characterized by deposition of cerebral amyloid-beta (A beta) and pancreatic human islet amyloid polypeptide (hIAPP), respectively. We investigated the role of amyloidogenic proteins in the interplay between these diseases. A novel double transgenic mouse model combining T2D and AD was generated and characterized. AD-related amyloid transgenic mice coexpressing hIAPP displayed peripheral insulin resistance, hyperglycemia, and glucose intolerance. A beta and IAPP amyloidco-deposition increased tau phosphorylation, and a reduction in pancreatic beta-cell mass was detected inislets. Increased brain A beta deposition and tau phosphorylation and reduced insulin levels and signaling were accompanied by extensive synaptic loss and decreased neuronal counts. Ab immunization rescued the peripheral insulin resistance and hyperglycemia, suggesting a role for A beta in T2D pathogenesis for individuals predisposed to AD. These findings demonstrate that Ab and IAPP are key factors in the overlapping pathologies of AD and T2D.

引用

页码：5409 / 5418

页数：10

共 51 条

[1] Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology [J].

Akter, Rehana ;

Cao, Ping ;

Noor, Harris ;

Ridgway, Zachary ;

Tu, Ling-Hsien ;

Wang, Hui ;

Wong, Amy G. ;

Zhang, Xiaoxue ;

Abedini, Andisheh ;

Schmidt, Ann Marie ;

Raleigh, Daniel P. .

JOURNAL OF DIABETES RESEARCH, 2016, 2016

[2] The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins [J].

Bharadwaj, Prashant ;

Wijesekara, Nadeeja ;

Liyanapathirana, Milindu ;

Newsholme, Philip ;

Ittner, Lars ;

Fraser, Paul ;

Verdile, Giuseppe .

JOURNAL OF ALZHEIMERS DISEASE, 2017, 59 (02) :421-432

[3] Role of RAGE in Alzheimer's Disease [J].

Cai, Zhiyou ;

Liu, Nannuan ;

Wang, Chuanling ;

Qin, Biyong ;

Zhou, Yingjun ;

Xiao, Ming ;

Chang, Liying ;

Yan, Liang-Jun ;

Zhao, Bin .

CELLULAR AND MOLECULAR NEUROBIOLOGY, 2016, 36 (04) :483-495

[4] Role of insulin resistance in Alzheimer's disease [J].

Cai, Zhiyou ;

Xiao, Ming ;

Chang, Liying ;

Yan, Liang-Jun .

METABOLIC BRAIN DISEASE, 2015, 30 (04) :839-851

[5] Mechanisms Linking Inflammation to Insulin Resistance [J].

Chen, Li ;

Chen, Rui ;

Wang, Hua ;

Liang, Fengxia .

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, 2015, 2015

[6] Oxidative stress in Alzheimer's disease [J].

Chen, Zhichun ;

Zhong, Chunjiu .

NEUROSCIENCE BULLETIN, 2014, 30 (02) :271-281

[7] Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695 [J].

Chishti, MA ;

Yang, DS ;

Janus, C ;

Phinney, AL ;

Horne, P ;

Pearson, J ;

Strome, R ;

Zuker, N ;

Loukides, J ;

French, J ;

Turner, S ;

Lozza, G ;

Grilli, M ;

Kunicki, S ;

Morissette, C ;

Paquette, J ;

Gervais, F ;

Bergeron, C ;

Fraser, PE ;

Carlson, GA ;

St George-Hyslop, P ;

Westaway, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (24) :21562-21570

[8] Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation [J].

Clarke, Julia R. ;

Lyra e Silva, Natalia M. ;

Figueiredo, Claudia P. ;

Frozza, Rudimar L. ;

Ledo, Jose H. ;

Beckman, Danielle ;

Katashima, Carlos K. ;

Razolli, Daniela ;

Carvalho, Bruno M. ;

Frazao, Renata ;

Silveira, Marina A. ;

Ribeiro, Felipe C. ;

Bomfim, Theresa R. ;

Neves, Fernanda S. ;

Klein, William L. ;

Medeiros, Rodrigo ;

LaFerla, Frank M. ;

Carvalheira, Jose B. ;

Saad, Mario J. ;

Munoz, Douglas P. ;

Velloso, Licio A. ;

Ferreira, Sergio T. ;

De Felice, Fernanda G. .

EMBO MOLECULAR MEDICINE, 2015, 7 (02) :190-210

[9] Inflammatory mechanisms in Alzheimer's disease:: Inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists [J].

Combs, CK ;

Johnson, DE ;

Karlo, JC ;

Cannady, SB ;

Landreth, GE .

JOURNAL OF NEUROSCIENCE, 2000, 20 (02) :558-567

[10] Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia [J].

Di Rosa, Michelino ;

Dell'Ombra, Nicola ;

Zambito, Anna Maria ;

Malaguarnera, Mariano ;

Nicoletti, Ferdinando ;

Malaguamera, Lucia .

EUROPEAN JOURNAL OF NEUROSCIENCE, 2006, 23 (10) :2648-2656

← 1 2 3 4 5 6 →