Hippocampal GABAergic neurons are susceptible to amyloid-β toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model.
The relevance of γ-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-β (Aβ) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Aβ42 (between 2 and 4 months) and accumulation of insoluble Aβ into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Aβ42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Aβ in vitro, GABAergic neurons are susceptible to Aβ42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Aβ load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5-2 month-old) TgCRND8 mice, it is likely that Aβ toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage.
Institut de Neurobiologie de la Méditerranée (INMED), U901, Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France. slavica.krantic@douglas.mcgill.ca
Slavica
S
Krantic
Nathalie
N
Isorce
Naguib
N
Mechawar
Maria Antonietta
MA
Davoli
Erika
E
Vignault
Marilia
M
Albuquerque
Jean-Guy
JG
Chabot
Emmanuel
E
Moyse
Jean-Pierre
JP
Chauvin
Isabelle
I
Aubert
Joanne
J
McLaurin
Rémi
R
Quirion
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D050598:Vesicular Glutamate Transport Protein 1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase