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Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease.
FASEB J. 2004 May; 18(7):902-4.FJ

Abstract

Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.

Authors+Show Affiliations

Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15033922

Citation

Ho, Lap, et al. "Diet-induced Insulin Resistance Promotes Amyloidosis in a Transgenic Mouse Model of Alzheimer's Disease." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 18, no. 7, 2004, pp. 902-4.
Ho L, Qin W, Pompl PN, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004;18(7):902-4.
Ho, L., Qin, W., Pompl, P. N., Xiang, Z., Wang, J., Zhao, Z., Peng, Y., Cambareri, G., Rocher, A., Mobbs, C. V., Hof, P. R., & Pasinetti, G. M. (2004). Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 18(7), 902-4.
Ho L, et al. Diet-induced Insulin Resistance Promotes Amyloidosis in a Transgenic Mouse Model of Alzheimer's Disease. FASEB J. 2004;18(7):902-4. PubMed PMID: 15033922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. AU - Ho,Lap, AU - Qin,Weiping, AU - Pompl,Patrick N, AU - Xiang,Zhongmin, AU - Wang,Jun, AU - Zhao,Zhong, AU - Peng,Yuanzhen, AU - Cambareri,Gina, AU - Rocher,Anne, AU - Mobbs,Charles V, AU - Hof,Patrick R, AU - Pasinetti,Giulio Maria, Y1 - 2004/03/19/ PY - 2004/3/23/pubmed PY - 2004/9/29/medline PY - 2004/3/23/entrez SP - 902 EP - 4 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 18 IS - 7 N2 - Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/15033922/Diet_induced_insulin_resistance_promotes_amyloidosis_in_a_transgenic_mouse_model_of_Alzheimer's_disease_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.03-0978fje?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -