Endogenous Galanin Protects Mouse Hippocampal Neurons Against Amyloid Toxicity in vitro via Activation of Galanin Receptor-2

Abstract

Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer’s disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β(Aβ) toxicity. Here we report that galanin or the GAL2/3-specific peptide agonist Gal2-11, both equally protect primary dispersed mouse wildtype (WT) neonatal hippocampal neurons from 250 nM Aβ1–42 toxicity in a dose dependent manner. The amount of Aβ1–42 induced cell death was significantly greater in mice with loss-of-function mutations in galanin (Gal-KO) or GAL2 (GAL2-MUT) compared to strain-matched WT controls. Conversely, cell death was significantly reduced in galanin over-expressing (Gal-OE) transgenic mice compared to strain-matched WT controls. Exogenous galanin or Gal2-11 rescued the deficits in the Gal-KO but not the GAL2-MUT cultures, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GAL2. Despite the high levels of endogenous galanin in the Gal-OE cultures, the addition of exogenous 100 nM or 50 nM galanin or 100 nM Gal2-11 further significantly reduced cell death, implying that GAL2-mediated neuroprotection is not at maximum in the Gal-OE mice. These data further support the hypothesis that galanin over-expression in AD is a neuroprotective response and imply that the development of a drug-like GAL2 agonist might reduce the progression of symptoms in patients with AD.

Elevated galanin may predict the risk of type 2 diabetes mellitus for development of Alzheimer’s disease

“…In vitro, administration of galanin or galanin (2-11) may rescue the neurotoxicity induced by Aβ (25-35) or Aβ (1-42) in rat primary cultured hippocampal neurons (Cheng and Yu, 2010;Elliott-Hunt et al, 2011). Similar results were also demonstrated using cultured human primary neurons (Cui et al, 2010).…”

“…These findings indicate that the actived GalR2/3 may involved in the protective effects against hippocampal Aβ aggregation(Cheng and Yu, 2010;Cui et al, 2010;Elliott-Hunt et al, 2011;Pirondi et al, 2010).Further studies demonstrated the ability of galanin to improve spatial memory impairment and to decrease hippocampal Aβ levels via activation of GalR2(Elliott-Hunt et al, 2007Li et al, 2013). On one hand, the levels of galanin and GalR2 mRNA were increased significantly in the hippocampus after Aβ administration, whereas GalR1 mRNA and protein levels were not changed(Li et al, 2013).…”

“…The galanin concentrations were higher in subjects with Alzheimer's disease or type 2 diabetes mellitus than healthy individuals. In turn, galanin may ameliorate both diseases through activation of central GalR2 (Elliott-Hunt et al, 2011;Fang et al, 2012b;Li et al, 2013). Thus, we propose that galanin may affect the relationship between Alzheimer's disease and type 2 diabetes mellitus directly and/or indirectly, in spite of its detailed mechanisms are not fully understood as yet.…”

“…On one hand, the levels of galanin and GalR2 mRNA were increased significantly in the hippocampus after Aβ administration, whereas GalR1 mRNA and protein levels were not changed(Li et al, 2013). On the other hand, the amount of Aβ(1-42) induced cell death was significantly greater in mice with loss-of-function mutations in galanin-knockout or GalR2 mutations compared to strain-matched mouse wildtype controls(Elliott-Hunt et al, 2011). Besides, exogenous galanin or galanin (2-11) rescued the deficits in the galanin-knockout but not the GalR2 mutations mice, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GalR2(Elliott-Hunt et al, 2011).…”

Characterization of the Rat GAL2R Promoter: Positive Role of ETS-1 in Regulation of the Rat GAL2R Gene in PC12 Cells

“…It has been shown that GAL2R can protect the hippocampus from neuronal damage and regulate the neurite outgrowth from adult sensory neurons in a PKC-dependent manner [22,23]. GAL2R can also influence neuronal survival and seizure-induced neurogenesis in the dentate gyrus [24].…”