Abstract
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 Aβ 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 (AβOs) 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-AβOs intrabody (scFvA13-KDEL), which selectively interferes with the intracellular generation of AβOs 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 AβOs 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 Aβ oligomers as a promising therapeutic target and prospects anti-AβOs scFvA13-KDEL intrabody as an effective tool for AD treatment.
Highlights
These authors contributed: Giovanni Meli, Raffaella Scardigli, Antonino CattaneoEdited by N
We demonstrated a severe impairment of subventricular zone (SVZ) adult neurogenesis (AN) in young Tg2576 mice, the earliest event observed in the neurodegeneration progression in this Alzheimer's disease (AD) model [26], and formally proved that this deficit is triggered by intracellular Aβ oligomers (AβOs)
We provided formal evidence of a causal link between the intracellular formation of toxic natural-occurring hAβOs in adult neural stem cells (aNSCs) and altered neurogenesis occurring prior to neurodegeneration
Summary
These authors contributed: Giovanni Meli, Raffaella Scardigli, Antonino Cattaneo. Different transgenic AD animal models show an altered neurogenesis in both SVZ and DG neurogenic niches, with a majority of studies reporting reduced neurogenesis and some others observing, instead, an increased generation of new neurons [10,11,12,13] These discrepancies might be due, in part, to the different timing of the observed AN alterations, with respect to the progression of neurodegeneration. According to the different hypotheses formulated about the role of neurogenesis in AD, enhanced AN might occur in diseased brain as a homeostatic selfrepair mechanism [14]; alternatively, decreased neurogenesis might contribute to the onset of neurodegeneration [15, 16] In this view, AD-causing molecules, such as the Amyloid-beta (Aβ) peptide, would deregulate AN, facilitating disease progression [17]. We investigated if intracellularly formed Aβ oligomers (AβOs) in Tg2576 modulate aNSCs biology in these mice, and provided a proof-of-concept for an innovative disease modifying approach based on intrabody conformational selective and subcellularly localized gene therapy
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