Title

Endogenous galanin protects mouse hippocampal neurons against amyloid toxicity in vitro via activation of galanin receptor-2

Document Type

Article

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.

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)

Publication Date

1-1-2011

Publication Title

Journal of Alzheimer's disease : JAD

E-ISSN

1875-8908

Volume

25

Issue

3

First Page

455

Last Page

62

PubMed ID

21471641

Digital Object Identifier (DOI)

10.3233/JAD-2011-110011

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