Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the Western world and is characterized by a progressive loss of cognitive functions leading to dementia. One major histopathological hallmark of AD is the formation of amyloid-beta plaques, which is reproduced in numerous transgenic animal models overexpressing pathogenic forms of amyloid precursor protein (APP). In human AD and in transgenic amyloid plaque mouse models, several studies report altered rates of adult neurogenesis, i.e. the formation of new neurons from neural stem and progenitor cells, and impaired neurogenesis has also been attributed to contribute to the cognitive decline in AD. So far, changes in neurogenesis have largely been considered to be a consequence of the plaque pathology. Therefore, possible alterations in neurogenesis before plaque formation or in prodromal AD have been largely ignored. Here, we analysed adult hippocampal neurogenesis in amyloidogenic mouse models of AD at different points before and during plaque progression. We found prominent alterations of hippocampal neurogenesis before plaque formation. Survival of newly generated cells and the production of new neurons were already compromised at this stage. Moreover and surprisingly, proliferation of doublecortin (DCX) expressing neuroblasts was significantly and specifically elevated during the pre-plaque stage in the APP-PS1 model, while the Nestin-expressing stem cell population was unaffected. In summary, changes in neurogenesis are evident already before plaque deposition and might contribute to well-known early hippocampal dysfunctions in prodromal AD such as hippocampal overactivity.
Highlights
Research Highlights Increased hippocampal neuroblast proliferation at pre-plaque stages
As there is increasing awareness for the importance of the pre-symptomatic phase in neurodegenerative diseases in the context of early diagnosis and of pathogenesis [reviewed in 37, 38], we investigated the temporal pattern of amyloid-beta plaque deposition in the hippocampus and analysed corresponding levels of adult hippocampal neurogenesis from very early prodromal to severe stages of amyloid-beta plaque formation in the amyloid precursor protein (APP) Swedish PS1 dE9 mouse model and in the slower progressing Tg2576 Alzheimer’s disease (AD) mouse model
Quantitative analysis of adult hippocampal neurogenesis in the granular cell layer (GCL) and subgranular cell layer (SGCL) of the dentate gyrus in the APP-PS1 mice and in Tg2576 mice was performed by immunohistochemistry
Summary
Research Highlights Increased hippocampal neuroblast proliferation at pre-plaque stages. Adult hippocampal neurogenesis is decreased in mice overexpressing the human APP with the Swedish mutation [31] but in mouse models harbouring the APP and the PS1 mutated genes decreased levels of neurogenesis [17] and increased levels of neurogenesis were reported in mice developing memory impairments and progressive plaque pathology [35]. As there is increasing awareness for the importance of the pre-symptomatic phase in neurodegenerative diseases in the context of early diagnosis and of pathogenesis [reviewed in 37, 38], we investigated the temporal pattern of amyloid-beta plaque deposition in the hippocampus and analysed corresponding levels of adult hippocampal neurogenesis from very early prodromal to severe stages of amyloid-beta plaque formation in the APP Swedish PS1 dE9 mouse model and in the slower progressing Tg2576 AD mouse model
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