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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Molecular Neurodegeneration 1/2017

Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer’s disease by compromising hippocampal inhibition

Zeitschrift:
Molecular Neurodegeneration > Ausgabe 1/2017
Autoren:
Carolyn Hollands, Matthew Kyle Tobin, Michael Hsu, Kianna Musaraca, Tzong-Shiue Yu, Rachana Mishra, Steven G. Kernie, Orly Lazarov
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13024-017-0207-7) contains supplementary material, which is available to authorized users.

Abstract

Background

The molecular mechanism underlying progressive memory loss in Alzheimer’s disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer’s disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis.

Methods

Here, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK).

Results

These animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1ΔE9 or δ-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted δ-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis.

Conclusions

These results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer’s disease.
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