Journal of Alzheimer's Disease - Volume 68, issue 4

Authors: Ju, Shiming | Xu, Chen | Wang, Gan | Zhang, Lin

Article Type: Research Article

Abstract: Traumatic brain injury (TBI), a brain disorder that causes death and long-term disability in humans, is increasing in prevalence, though there is a lack of protective or therapeutic strategies for mitigating the damage after TBI and for preserving neurological functionality. Microglia cells play a key role in neuroinflammation following TBI, but their regulation and polarization by a member of the vascular endothelial growth factor (VEGF) family, VEGF-C, is unknown. Here, we show that VEGF-C induced M2 polarization in a murine microglia cell line, BV-2, in vitro , by a mechanism that required signaling from its unique receptor, VEGF receptor 3 …(VEGFR3). Moreover, in a TBI model in rats, VEGF-C administration induced M2 polarization of microglia cells, significantly improved motor deficits after experimental TBI, and significantly improved neurological function following TBI, likely through a reduction in cell apoptosis. Together, our data reveal a previously unknown role of VEGF-C/VEGFR3 signaling in the regulation of post-TBI microglia cell polarization, which appears to be crucial for recovery from TBI. Show more

Keywords: Microglia, polarization, traumatic brain injury, VEGF-C, VEGFR3

DOI: 10.3233/JAD-190063

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1687-1697, 2019

Authors: Farr, Susan A. | Roesler, Elizabeth | Niehoff, Michael L. | Roby, Deborah A. | McKee, Alexis | Morley, John E.

Article Type: Research Article

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-3β ser9, pGSK-3β tyr216, 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-3β ser9 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 p Tau. The current study lends support to the therapeutic potential of metformin for AD. Show more

Keywords: Learning, memory, metformin, PKC, SAMP8, tau

DOI: 10.3233/JAD-181240

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1699-1710, 2019