Abstract
Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer’s disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer’s disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.
Highlights
Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder that is the most common form of dementia
We found that cell proliferation was decreased in the amyloid precursor protein (APP)/PS1 mice, but this was rescued by the overexpression of sAPPα-treated mice were immunolabelled with mouse anti-6E10 (sAPPα)
We found that sAPPα overexpression increased astrocytic, but not neuronal survival in the granule cell layer (GCL) of APP/PS1 mice. sAPPα overexpression increased astrocytic differentiation, as indicated by the percentage of adult-born astrocytes in the GCL irrespective of genotype
Summary
Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder that is the most common form of dementia. It is characterised by a build-up of toxic soluble oligomers of the amyloid-β (Aβ) peptide (both intra- and extracellularly), aggregation of the Aβ into. Ohline et al Molecular Brain (2022) 15:5 in AD centres on the amyloid cascade hypothesis [2]. This states that the over-accumulation of Aβ, either by enhanced cleavage of the parent protein amyloid precursor protein (APP), or by decreased clearance, is a critical step in developing AD. The γ/β secretases release the Aβ fragment and the N-terminal fragment sAPPβ, whereas α-secretase cleavage within the Aβ peptide sequence prevents its production and releases the larger N-terminal fragment soluble amyloid precursor protein-alpha (sAPPα). sAPPα differs from sAPPβ by only a 16 amino acid extension at its C-terminus, but is generally 100-fold more potent in regulating neuronal function [6]
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