Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

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.

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Of particular relevance here is that adult neurogenesis is linked to AD [149,150], and impaired adult neurogenesis could be an early event in AD [151]. Conceivably, neuronal vulnerability to AD etiology may be exacerbated by earlier defects in the progenitor cells, while adult neurogenesis could be a compensatory response to neuronal loss to the disease condition.…”

The Microalgae Aurantiochytrium Sp. Increases Neurogenesis and Improves Spatial Learning and Memory in Senescence-Accelerated Prone 8 Mice

“…Numerous studies have demonstrated the neuroprotective effects of nutraceuticals against toxic compounds associated with neurodegenerative diseases, via mechanisms such as modulation of energy metabolism, oxidative stress, neuroin ammation as well as promotion of neurogenesis via growth factors and neurotrophins [22,23]. In particular, the relationship between adult neurogenesis and AD has been debated in recent years [24,25]. Previous studies have reported that the reduction of expression of neurogenesis markers in the SVZ and DG regions of post-mortem AD brain.…”

Neuroinflammation and Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

“…Other APP metabolites, such as sAPP-α, sAPP-β, Aβ peptides, and APP intracellular C-terminal domain (AICD) appear to modulate various functions in NSCs, including proliferation, neurogenesis, gliogenesis, or cell death [139]. Scopa, et al [140] reported neurogenesis defects in a prodromal asymptomatic age (1.5 months of age) of TG2576 transgenic mice, in which the proliferation of NSCs was significantly reduced and the NSCs failed to differentiate into mature neurons. This reduction depended on the formation and accumulation of intracellular Aβ oligomers in NSCs, indicating the negative impact of Aβ oligomers on neurogenesis.…”