Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here

Hamilton, Laura; Joppé, Sandra E.; Cochard, Loïc M.; Fernandes, Karl J.L.

doi:10.1111/ejn.12326

Cited by 12 publications

(17 citation statements)

References 2 publications

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“…The aim of this approach was to identify key transcriptional changes underlying the decline in the activity and loss of competence of NSCs that occurs in adulthood, which is attributed to the combined up-regulation of inhibitory and down-regulation of positive cues [30], and is critical for the response of NSCs to brain injury and degeneration [31,32]. In this manner, key small molecules were identified for “rejuvenating” adult NSC (Fig 2E; Table 1D), approximately 20% of which overlapped with those required in dorsalizing or ventralizing the postnatal SVZ, and were categorized as “Receptor antagonist,” “Signaling,” and “Metabolism.” Some interesting candidates included antagonists for α/β adrenergic receptors, including the highly ranked nadolol (Table 1D), which have been described to promote NSC activation from quiescence in the dentate gyrus [33] and enhance NP survival following exit from the SVZ [34].…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of BAT-gal mice [41] further demonstrated a decline in Wnt/β-catenin activity between P6 and P60, together with a decrease in the densities of Tbr2+ NPs and to a lesser extent Olig2+ OPs in the adult and their apparent loss by P120 (Fig 6B and 6C). These analyses reveal that the neurogenic capacity and lineage diversity of the dSVZ declines in the adult brain [30,42] and, based on the SPIED/CMAP analysis, we predicted GSK3β inhibitors are strong candidates for rejuvenating the adult dSVZ.…”

Section: Resultsmentioning

confidence: 99%

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Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity

et al. 2017

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Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity

et al. 2017

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“…The NSCs ensure brain homeostasis, repair, and neuroregeneration in the adult, but undergo proliferation and differentiation decline with age. The decreased neurogenesis correlates and contributes to age‐related disorders in the human and in mouse model, and it is thought to be due to the senescence of progenitor cells. Diverse stimuli can induce senescence in NSCs in vitro, including DNA damage, oxidative stress, and activated oncogenes .…”

Section: Senescence In the Brain And Its Physiological Rolementioning

confidence: 99%

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Spinelli

Martucciello

Nori

et al. 2018

Journal of Leukocyte Biology

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Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes throughout life is coming to light. The "senescence machinery" has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the beneficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases.

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“…In addition, following neural damage, NSC-derived progeny are re-directed to areas of degeneration, where they are involved in wound healing and cell replacement and can serve as a target for therapeutic manipulations (Benner et al, 2013;de Chevigny et al, 2008;Erlandsson et al, 2011;Kolb et al, 2007). NSC activity decreases naturally during aging and is dysregulated in models of neurodegenerative diseases, suggesting an involvement in aging-and disease-associated cognitive deficits (Bouab et al, 2011;Demars et al, 2010;Hamilton et al, 2010;Hamilton et al, 2013;Lazarov and Marr, 2010;. Consistent with this, disturbances in neurogenesis have been reported in Alzheimer's disease (AD) patients (Crews et al, 2010;Perry et al, 2012;Ziabreva et al, 2006) and a range of AD transgenic mouse models (Chuang, 2010;Hamilton et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

et al. 2015

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Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.

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Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here

Cited by 12 publications

References 2 publications

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

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