Adult hippocampal neurogenesis and its role in Alzheimer's disease

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD

Neurogenic niche modulation by activated microglia: Transforming growth factor β increases neurogenesis in the adult dentate gyrus

Adult neural stem cells (NSC) proliferate and differentiate depending on the composition of the cellular and molecular niche in which they are immersed. Until recently, microglial cells have been ignored as part of the neurogenic niche. We studied the dynamics of NSC proliferation and differentiation in the dentate gyrus of the hippocampus (DG) and characterized the changes of the neurogenic niche in adrenalectomized animals (ADX). At the cellular level, we found increased NSC proliferation and neurogenesis in the ADX animals. In addition, a morphologically distinct subpopulation of NSC (Nestin+/GFAP-) with increased proliferating profile was detected. Interestingly, the number of microglial cells at stages 2 and 3 of activation correlated with increased neurogenesis (r2 = 0.999) and the number of Nestin-positive cells (r2 = 0.96). At the molecular level, transforming growth factor beta (TGF-β) mRNA levels were increased 10-fold in ADX animals. Interestingly, TGF-β levels correlated with the amount of neurogenesis detected (r 2 = 0.99) and the number of stage 2 and 3 microglial cells (r 2 = 0.94). Furthermore, blockade of TGF-β biological activity by administration of an anti-TGF-β type II receptor antibody diminished the percentage of 5-bromo-2′-deoxyuridine (BrdU)/q1PSA-NCAM-positive cells in vivo. Moreover, TGF-β was able to promote neurogenesis in NSC primary cultures. This work supports the idea that activated microglial cells are not pro- or anti-neurogenic per se, but the balance between pro- and anti-inflammatory secreted molecules influences the final effect of this activation. Importantly, we identified an anti-inflammatory cytokine, TGF-β, with neurogenic potential in the adult brain.Fil: Battista, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferrari, Carina Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Gage, Fred H.. Salk Institute for Biological Studies; Estados UnidosFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size.

Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.T.O. was supported by the Wellcome Trust PhD Programme in Developmental Biology at the University of Cambridge. F.J.L. and B.D.S. are Wellcome Trust Investigators. This research was supported by core funding to the Gurdon Institute by the Wellcome Trust and Cancer Research UK. F.H.G. was supported by the Helmsley, Mathers, and JPB Foundations.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.stem.2016.03.00

Enhanced Survival and Neuronal Differentiation of Adrenal Chromaffin Cells Cografted into the Striatum with NGF-producing Fibroblasts

Although adrenal medullary chromaffin cells have been used extensively for intracerebral grafting, their survival has generally been poor. Improved survival of the implanted cells has been achieved by exposing the chromaffin cells to NGF in vivo. Culture studies have shown, however, that chromaffin cells are converted into sympathetic neurons when NGF is included in the medium. The degree to which such a transdifferentiation may occur in vivo has not been determined. We assessed the effects of cografting chromaffin cells with primary fibroblasts genetically engineered to express NGF. Chromaffin cells from 10 d old rats were implanted with NGF-producing or beta- galactosidase-producing primary fibroblasts (control fibroblasts) into the striatum of 6-hydroxydopamine treated adult rats of the same strain. Eight weeks postgrafting, chromaffin cells cografted with NGF- producing fibroblasts displayed many of the features of mature sympathetic neurons such as large somata, long processes, transmitter vesicles similar to those found in neurons, and positive immunolabeling for the neuronal markers neurofilament, MAP2 and SCG10. Chromaffin- derived neuron number was also significantly enhanced in the presence of NGF-producing fibroblasts. While control fibroblasts were also found to increase chromaffin cell number above that of chromaffin cells grafted alone, the control fibroblasts did not induce neuronal transdifferentiation. These results demonstrate that chromaffin cells cografted with NGF-producing fibroblasts undergo transdifferentiation in vivo and express many characteristics of mature sympathetic neurons. The consequences of this transdifferentiation on the long term survival and function of the transplanted cells in vivo remain to be clarified

IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes

Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage

Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases.

Most of our current knowledge about cellular phenotypes in neurodevelopmental and neurodegenerative diseases in humans was gathered from studies in postmortem brain tissues. These samples often represent the end-stage of the disease and therefore are not always a fair representation of how the disease developed. Moreover, under these circumstances, the pathology observed could be a secondary effect rather than the authentic disease cellular phenotype. Likewise, the rodent models available do not always recapitulate the pathology from human diseases. In this review, we will examine recent literature on the use of induced pluripotent stem cells to model neurodegenerative and neurodevelopmental diseases. We highlight the characteristics of diseases like spinal muscular atrophy and familial dysautonomia that allowed partial modeling of the disease phenotype. We review human stem cell literature on common neurodegenerative late-onset diseases such as Parkinson's disease and amyotrophic lateral sclerosis where patients' cells have been successfully reprogrammed but a disease phenotype has not yet been described. So far, the technique is of great interest for early onset monogenetic neurodevelopmental diseases. We speculate about potential further experimental requirements and settings for reprogrammed neurons for in vitro disease modeling and drug discovery

Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories.

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. The computational process for making representations of similar input patterns more distinct from each other has been referred to as "pattern separation." Although adult-born immature neurons have been implicated in this memory feature, the precise role of these neurons and associated molecules in the processing of overlapping memories is unknown. Recently, we found that brain-derived neurotrophic factor (BDNF) in the dentate gyrus is required for the encoding/consolidation of overlapping memories. In this study, we provide evidence that consolidation of these "pattern-separated" memories requires the action of BDNF on immature neurons specifically.The Biotechnology and Biological Sciences Research Council . Grant Number: BB/G019002/1 The Innovative Medicine Initiative Joint Undertaking . Grant Number: 115008 The European Union's Seventh Framework Programme . Grant Number: FP7/2007-2013 The James S. McDonnell Foundation, Mather's Foundation, NIMH, Ellison Foundation, NINDS, NIMH, NIA, JPB FoundationThis is the final published version, which can also be viewed online at: http://onlinelibrary.wiley.com/doi/10.1002/hipo.22304/ful