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Effect of soluble amyloid precursor protein-alpha on adult hippocampal neurogenesis in a mouse model of Alzheimer's disease.

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.

SUBMITTER: Ohline SM

PROVIDER: S-EPMC8721980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Amyloid precursor protein (APP), a key molecule in Alzheimer's disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPP?). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPP? in CSF as a biomarker has not been clearly established. sAPP? has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required. METHODS: The tests are based on homogenous time-resolved fluorescence and require no washing steps. RESULTS: We describe two new rapid and sensitive tests for quantifying mouse and human sAPP?. These 20 ?l-volume tests quantify the levels of: i) endogenous mouse sAPP? in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPP? in the CSF of AD mouse models, and iii) human sAPP? in the CSF of AD and non-AD patients. These tests require only 5??l of conditioned medium from 5 × 10(4) mouse primary neurons, 1??l of CSF from wild-type and transgenic mice, and 0.5??l of human CSF. CONCLUSIONS: The high sensitivity of the mouse sAPP? test will allow high-throughput investigations of molecules capable of increasing the secretion of endogenous sAPP? in primary neurons, as well as the in vivo validation of molecules of interest through the quantification of sAPP? in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPP? in the CSF through the progression of the disease. Finally, the human sAPP? test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies.

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Effect of soluble amyloid precursor protein-alpha on adult hippocampal neurogenesis in a mouse model of Alzheimer's disease.

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