Amyloid β precursor protein regulates neuron survival and maturation in the adult mouse brain

Abstract

The amyloid-β precursor protein (APP) is a transmembrane protein that is widely expressed within the central nervous system (CNS). While the pathogenic dysfunction of this protein has been extensively studied in the context of Alzheimer's disease, its normal function is poorly understood, and reports have often appeared contradictory. In this study we have examined the role of APP in regulating neurogenesis in the adult mouse brain by comparing neural stem cell proliferation, as well as new neuron number and morphology between APP knockout mice and C57bl6 controls. Short-term EdU administration revealed that the number of proliferating EdU⁺ neural progenitor cells and the number of PSA-NCAM⁺ neuroblasts produced in the SVZ and dentate gyrus were not affected by the life-long absence of APP. However, by labelling newborn cells with EdU and then following their fate over-time, we determined that ~48% more newly generated EdU⁺ NeuN⁺ neurons accumulated in the granule cell layer of the olfactory bulb and ~57% more in the dentate gyrus of young adult APP knockout mice relative to C57bl6 controls. Furthermore, proportionally fewer of the adult-born olfactory bulb granule neurons were calretinin⁺. To determine whether APP was having an effect on neuronal maturation, we administered tamoxifen to young adult Nestin-CreER^T2::Rosa26-YFP and Nestin-CreER^T2::Rosa26-YFP::APP-knockout mice, fluorescently labelling ~80% of newborn (EdU⁺) NeuN⁺ dentate granule neurons formed between P75 and P105. Our analysis of their morphology revealed that neurons added to the hippocampus of APP knockout mice have shorter dendritic arbors and only half the number of branch points as those generated in C57bl6 mice. We conclude that APP reduces the survival of newborn neurons in the olfactory bulb and hippocampus, but that it does not influence all neuronal subtypes equally. Additionally, APP influences dentate granule neuron maturation, acting as a robust regulator of dendritic extension and arborisation.

Keywords: APP; Amyloid β precursor protein; Dendrites; Hippocampus; Interneurons; Lineage tracing; Maturation; Neural stem cells; Proliferation; SVZ; Survival.