Hippocampal Radial Glial Subtypes and Their Neurogenic Potential in Human Fetuses and Healthy and Alzheimer’s Disease Adults

Abstract

Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPδ+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult.

Transcriptomic Analysis of the Neurogenesis Signature suggests Continued but Minimal Neurogenesis in the Adult Human Hippocampus

“…Cipriani et al (3)(4)(5), that there is absolute post childhood seize in formation of new neurons, though we support the notion that a significant proportion of the new formed cells in the neurogenic niche may be the glial cells. We conclude that an active but minimal hippocampal neurogenesis is possibly continued in adult human.…”

“…Studies with contrasting evidence have emerged since then which ranged from absolute denial (3)(4)(5) to approval for the persistence of AHN even in old individuals (6)(7)(8). In adult mammals (including human) neurogenesis is thought to persist in the subgranular zone (SGZ) of the dentate gyrus (DG) region of the hippocampus (9).…”

“…Dennis et al, 2016 denied AHN in humans using immunohistological methods in postmortem samples across different age groups (4). The most robust disapproval, however, has appeared recently from Sorrells et al (3), and it has been followed by a similar denial from Cipriani et al (5), who based their conclusions on a more comprehensive use of immunohistological and ultrastructural methods, and in a greater diversity of samples. All three AHN negative studies shared the view that if any newly formed cells in the neurogenic niche are found, those are actually glial cells.…”

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

“…This understanding would be instrumental in designing targeted therapy options for AD in humans and may lead to more detailed analyses of NSC subtypes in experimental mammalian models of AD. Additionally, the role of Interleukin-4 and Serotonin in regulating diverse signaling mechanisms in NSCs opens up interesting research avenues as to whether modulation of neuroinflammatory milieu in mammalian brains would kick-start a "regeneration" response by mobilizing the endogenous reservoir of NSCs, which is a controversial subject (Arellano et al, 2018;Cipriani et al, 2018;Rodriguez and Verkhratsky, 2011;Sorrells et al, 2018;Tincer et al, 2016;Waldau and Shetty, 2008;Ziabreva et al, 2006). We propose that zebrafish can be used to address neurogenesis-related questions in disease conditions and could serve as a useful experimental model for investigating the molecular mechanisms of neural stem cell plasticity.…”

“…An alternative approach was suggested to be to complement the treatment in neuronal compartments with increasing the production of new neurons to provide resilience and strength to the diseased circuitry (Choi et al, 2018;Moreno-Jimenez et al, 2019;Mu and Gage, 2011;Tincer et al, 2016). Yet, neurogenesis in human brains is quite controversial (Arellano et al, 2018;Cipriani et al, 2018;Dennis et al, 2016;Duque and Spector, 2019;Sorrells et al, 2018). Although many reports documented the presence of adult neurogenesis in human brains (Boldrini et al, 2018;Ernst et al, 2014;Kempermann et al, 2018;Magnusson and Frisen, 2016;Moreno-Jimenez et al, 2019;Spalding et al, 2013), and several studies demonstrated that boosting the neurogenesis might be a viable option for alleviating the cognitive decline (Casse et al, 2018;Choi et al, 2018;Martinez-Canabal, 2014;Papadimitriou et al, 2018;Rodriguez and Verkhratsky, 2011), the potential benefits of neurogenic outcome in AD conditions requires further investigation and critical testing.…”