Abstract
Alzheimer's disease (AD), the most common cause of dementia, is characterised by amyloid-beta accumulation, phosphorylated tau aggregation, neuroinflammation and neurodegeneration in the brain. Current therapies targeted at reducing amyloid-beta have not proven effective yet, warranting research into other avenues. The hippocampus contains neural stem cells that continuously generate new neurons throughout adulthood, a process known as adult hippocampal neurogenesis (AHN). Increasing evidence indicates that AHN, proposed to play important roles in hippocampus-dependent learning and memory, is impaired in AD mouse models and in humans with AD. The neuroprotective protein secreted amyloid precursor protein-alpha (sAPPα), a product of non-amyloidogenic APP processing, enhances memory and stimulates neurogenesis in vitro. The present study investigated whether the genesis of neurons or astrocytes is impaired in the APP/PS1 transgenic (Tg) mouse model of AD and whether sAPPα overexpression could rescue neuro- and astrogenesis in vivo. Three phases of AHN, cell proliferation, differentiation and survival of neurons and astrocytes, were assessed in the dentate gyrus (DG) of adult female APP/PS1 and wild-type (WT) mice. Two further questions were asked: (i) whether sAPPα overexpression induced differences in AHN along the longitudinal axis of the hippocampus and (ii) whether sAPPα overexpression attenuated amyloid plaque burden in the DG.
To address the aims of the study, adeno-associated viral vectors (AAV) encoding HA-tagged sAPPα (APP695) or enhanced green fluorescent protein (EGFP control) were injected bilaterally into the dorsal DG of the hippocampi of 8-month-old female mice. After birth dating both proliferating and surviving adult-born cells with thymidine analogues (XdU) immunofluorescence revealed Tg-control mice had a ~71% reduction of newly proliferated progenitor cell density in the DG subgranular zone that was rescued by sAPPα overexpression by ~61%.
In APP/PS1 mice, no change in the differentiation of adult-born astrocytes and neurons in the granule cell layer (GCL) was discovered but sAPPα overexpression increased astrocytic differentiation in the GCL. Survival of adult-born cells, including neurons and astrocytes, was impaired, and sAPPα overexpression increased astrocytic, but not neuronal survival in the GCL of APP/PS1 mice. For WT mice, sAPPα overexpression increased adult-born cell proliferation, astrocytic differentiation, and survival in the GCL, but not neuronal differentiation and survival. sAPPα overexpression also reduced amyloid burden in the DG and cortex, confirming its ability to reduce amyloid in an Alzheimer's mouse model.
The results indicate that adult female APP/PS1 mice had a cell proliferation impairment that was rescued by sAPPα overexpression. Neuro- and astrogenesis in surviving adult-born cells were impaired overall in APP/PS1 mice. sAPPα overexpression had a stronger proliferative effect on adult-born cells compared to a neurogenic effect, suggesting that sAPPα overexpression can be adapted for future manipulations to increase neurogenesis preferentially. The present study provides a novel proof-of-principle that sAPPα overexpression in vivo can be used to increase astrogenesis in an AD context. This may help to develop therapeutic approaches for modifying the course of AD or disorders involving cell loss.