Hippocampal GABAergic Neurons are Susceptible to Amyloid-β Toxicity in vitro and are Decreased in Number in the Alzheimer's Disease TgCRND8 Mouse Model

Abstract

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.