Affiliations: [a] Research and Development Service, VA Medical Center, MO, USA
| [b] Division of Geriatric Medicine, Saint Louis University School of Medicine, MO, USA
| [c] Department of Pharmacology and Physiology, Saint Louis University School of Medicine, MO, USA
| [d] Division of Endocrinology, Diabetes, and Metabolism, Saint Louis University, MO, USA
Correspondence:
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Correspondence to: Susan A. Farr, PhD, Research Health Scientist/Professor, VA Medical Center St. Louis, MO/Division of Geriatric Medicine, St. Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO 63104, USA. Tel.: +1 314 977 6084; E-mail: susan.farr@health.slu.edu.
Abstract: Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer’s disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCɛ), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.
Keywords: Learning, memory, metformin, PKC, SAMP8, tau
