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

Abstract

BackgroundThe 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.MethodsHere, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK).ResultsThese 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0207-7) contains supplementary material, which is available to authorized users.

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

“…These discrepancies might be due, in part, to the different timing of the observed AN alterations, with respect to the progression of neurodegeneration. According to the different hypotheses formulated about the role of neurogenesis in AD, enhanced AN might occur in diseased brain as a homeostatic selfrepair mechanism [14]; alternatively, decreased neurogenesis might contribute to the onset of neurodegeneration [15,16]. In this view, AD-causing molecules, such as the Amyloid-beta (Aβ) peptide, would deregulate AN, facilitating disease progression [17].…”

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

“…That male, but not female, mice show both loss of NSCs and decreased performance in the task subsequent to the loss of the α7 nAChR is an intriguing correlation, but more research is needed to determine whether the effect seen is the direct result of changes in neurogenesis after loss of α7 nAChRs. Multiple previous studies show an association between levels of adult neurogenesis and performance in tasks measuring pattern separation, spatial discrimination, or cognitive flexibility (Clelland et al 2009; Cushman et al 2012; Hollands et al 2017; Pan et al 2012; Sahay et al 2011). Previous studies in rats and voles have shown the hippocampus to be a sexually dimorphic structure (Galea 2008; Luine et al 2017).…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Of particular relevance here is that adult neurogenesis is linked to AD [149,150], and impaired adult neurogenesis could be an early event in AD [151]. Conceivably, neuronal vulnerability to AD etiology may be exacerbated by earlier defects in the progenitor cells, while adult neurogenesis could be a compensatory response to neuronal loss to the disease condition.…”