Endogenous galanin protects mouse hippocampal neurons against amyloid toxicity in vitro via activation of galanin receptor-2
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.
Medical Subject Headings
Amyloid beta-Peptides (toxicity); Analysis of Variance; Animals; Animals, Newborn; Cell Death (drug effects, genetics); Cells, Cultured; Dose-Response Relationship, Drug; Galanin (genetics, metabolism, pharmacology); Glutamic Acid (toxicity); Hippocampus (cytology); Mice; Mice, Transgenic; Neurons (drug effects, metabolism); Peptide Fragments (pharmacology, toxicity); Receptor, Galanin, Type 2 (deficiency, metabolism)
Journal of Alzheimer's disease : JAD
Digital Object Identifier (DOI)
Elliott-Hunt, Caroline R.; Holmes, Fiona E.; Hartley, Dean M.; Perez, Sylvia; Mufson, Elliott J.; and Wynick, David, "Endogenous galanin protects mouse hippocampal neurons against amyloid toxicity in vitro via activation of galanin receptor-2" (2011). Translational Neuroscience. 1795.