GLP-1 Receptor Stimulation Reduces Amyloid-β Peptide Accumulation and Cytotoxicity in Cellular and Animal Models of Alzheimer's Disease

Article type: Research Article

Authors: Li, Yazhou^a | Duffy, Kara B.^b | Ottinger, Mary Ann^b | Ray, Balmiki^c | Bailey, Jason A.^c | Holloway, Harold W.^a | Tweedie, David^a | Perry, TracyAnn^a | Mattson, Mark P.^a | Kapogiannis, Dimitrios^a | Sambamurti, Kumar^d | Lahiri, Debomoy K.^c | Greig, Nigel H.^{a; *}

Affiliations: [a] Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD, USA | [b] Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA | [c] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Physiology & Neuroscience, Medical University of South Carolina, Charleston, SC, USA

Correspondence: [*] Correspondence to: Nigel Greig, Drug Design & Development Section, Laboratory of Neuroscience, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224, USA. Tel.: +1 410 558 8278; Fax: +1 410 558 8323; E-mail: greign@grc.nia.nih.gov.

Abstract: Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-β protein (Aβ) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Aβ and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Aβ protein precursor and Aβ, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

Keywords: 3xTg-AD mice, Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, dementia, diabetes, extendin-4, glucagon-like peptide-1, neuroprotection, streptozocin, tau

DOI: 10.3233/JAD-2010-1314

Journal: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1205-1219, 2010