| First Author | Scopa C | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 3 | Pages | 934-948 |
| PubMed ID | 31591472 | Mgi Jnum | J:296462 |
| Mgi Id | MGI:6467720 | Doi | 10.1038/s41418-019-0409-3 |
| Citation | Scopa C, et al. (2020) Impaired adult neurogenesis is an early event in Alzheimer's disease neurodegeneration, mediated by intracellular Abeta oligomers. Cell Death Differ 27(3):934-948 |
| abstractText | Alterations of adult neurogenesis have been reported in several Alzheimer's disease (AD) animal models and human brains, while defects in this process at presymptomatic/early stages of AD have not been explored yet. To address this, we investigated potential neurogenesis defects in Tg2576 transgenic mice at 1.5 months of age, a prodromal asymptomatic age in terms of Abeta accumulation and neurodegeneration. We observe that Tg2576 resident and SVZ-derived adult neural stem cells (aNSCs) proliferate significantly less. Further, they fail to terminally differentiate into mature neurons due to pathological, tau-mediated, and microtubule hyperstabilization. Olfactory bulb neurogenesis is also strongly reduced, confirming the neurogenic defect in vivo. We find that this phenotype depends on the formation and accumulation of intracellular A-beta oligomers (AbetaOs) in aNSCs. Indeed, impaired neurogenesis of Tg2576 progenitors is remarkably rescued both in vitro and in vivo by the expression of a conformation-specific anti-AbetaOs intrabody (scFvA13-KDEL), which selectively interferes with the intracellular generation of AbetaOs in the endoplasmic reticulum (ER). Altogether, our results demonstrate that SVZ neurogenesis is impaired already at a presymptomatic stage of AD and is caused by endogenously generated intracellular AbetaOs in the ER of aNSCs. From a translational point of view, impaired SVZ neurogenesis may represent a novel biomarker for AD early diagnosis, in association to other biomarkers. Further, this study validates intracellular Abeta oligomers as a promising therapeutic target and prospects anti-AbetaOs scFvA13-KDEL intrabody as an effective tool for AD treatment. |
