title: 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.
authors.affiliation: Schools of Physiology and Pharmacology and Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Elliott-Hunt
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Holmes
authors.forename: Dean M
authors.initials: DM
authors.lastname: Hartley
authors.forename: Sylvia
authors.initials: S
authors.lastname: Perez
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: David
authors.initials: D
authors.lastname: Wynick
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019004:Galanin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000633:toxicity*; D044092:Receptor, Galanin, Type 2 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D044092:Receptor, Galanin, Type 2; C075222:amyloid beta-protein (1-42); C434734:galanin (2-11)-amide; D018698:Glutamic Acid; D019004:Galanin