Star W. Lee

Signaling in adult neurogenesis

Neural stem cells (NSCs) in the adult brain continuously supply new neurons to the hippocampal dentate gyrus (DG) and the olfactory bulb (OB). Recent studies indicate that the progression from neural precursor cells (NPCs) to mature neurons is tightly controlled by coordinate cell-intrinsic programs and external signals within the neurogenic niche. In this review, we summarize both classes of regulatory factors involved in distinct stages of adult neurogenesis, including proliferation and lineage differentiation of NSCs, migration of neuroblasts and integration of newborn neurons. A full understanding of the wide variety of signaling pathways will ultimately provide precise targets for therapeutic applications.

New neurons in an aged brain

Adult hippocampal neurogenesis is one of the most robust forms of synaptic plasticity in the nervous system and occurs throughout life. However, the rate of neurogenesis declines dramatically with age. Older animals have significantly less neural progenitor cell proliferation, neuronal differentiation, and newborn neuron survival compared to younger animals. Intrinsic properties of neural progenitor cells, such as gene transcription and telomerase activity, change with age, which may contribute to the observed decline in neurogenesis. In addition, age-related changes in the local cells of the neurogenic niche may no longer provide neural progenitor cells with the cell-cell contact and soluble cues necessary for hippocampal neurogenesis. Astrocytes, microglia, and endothelial cells undergo changes in morphology and signaling properties with age, altering the foundation of the neurogenic niche. While most studies indicate a correlation between decreased hippocampal neurogenesis and impaired performance in hippocampus-dependent cognitive tasks in aged mice, a few have demonstrated that young and aged mice are equivalent in their cognitive ability. Here, we summarize the different behavioral paradigms to test hippocampus-dependent cognition and the need to develop neurogenesis-dependent tasks.

The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain

Background and Purpose— The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia. Methods— Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2−/− reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test. Results— Using NSC isolated from CCR2+/+ and CCR2−/− mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2−/− mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2−/− cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2−/− NSC. Conclusions— The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.

Mitochondrial Protection Attenuates Inflammation-Induced Impairment of Neurogenesis In Vitro and In Vivo

The impairment of hippocampal neurogenesis has been linked to the pathogenesis of neurological disorders from chronic neurodegenerative disease to the progressive cognitive impairment of children who receive brain irradiation. Numerous studies provide evidence that inflammation downregulates neurogenesis, with multiple factors contributing to this impairment. Although mitochondria are one of the primary targets of inflammatory injury, the role of mitochondrial function in the modulation of neurogenesis remains relatively unstudied. In this study, we used neurosphere-derived cells to show that immature doublecortin (Dcx)-positive neurons are uniquely sensitive to mitochondrial inhibition, demonstrating rapid loss of mitochondrial potential and cell viability compared with glial cells and more mature neurons. Mitochondrial inhibition for 24 h produced no significant changes in astrocyte or oligodendrocyte viability, but reduced viability of mature neurons by 30%, and reduced survival of Dcx+ cells by 60%. We demonstrate that protection of mitochondrial function with mitochondrial metabolites or the mitochondrial chaperone mtHsp75/mortalin partially reverses the inflammation-associated impairment of neurogenesis in vitro and in irradiated mice in vivo. Our findings highlight mitochondrial mechanisms involved in neurogenesis and indicate mitochondria as a potential target for protective strategies to prevent the impairment of neurogenesis by inflammation.

PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness.

The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused an ∼50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.

MHC mismatch inhibits neurogenesis and neuron maturation in stem cell allografts.

Background The role of histocompatibility and immune recognition in stem cell transplant therapy has been controversial, with many reports arguing that undifferentiated stem cells are protected from immune recognition due to the absence of major histocompatibility complex (MHC) markers. This argument is even more persuasive in transplantation into the central nervous system (CNS) where the graft rejection response is minimal. Methodology/Principal Findings In this study, we evaluate graft survival and neuron production in perfectly matched vs. strongly mismatched neural stem cells transplanted into the hippocampus in mice. Although allogeneic cells survive, we observe that MHC-mismatch decreases surviving cell numbers and strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. Immune suppression with cyclosporine-A did not improve outcome but non-steroidal anti-inflammatory drugs, indomethacin or rosiglitazone, were able to restore allogeneic neuron production, integration and retention to the level of syngeneic grafts. Conclusions/Significance These results suggest an important but unsuspected role for innate, rather than adaptive, immunity in the survival and function of MHC-mismatched cellular grafts in the CNS.

Enrichment rescues contextual discrimination deficit associated with immediate shock

Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE‐induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear‐conditioning (FC) procedure to tease out the behavioral differences between RUN‐induced neurogenesis and EE‐induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE‐induced neurogenesis, suggesting a fundamental functional difference between RUN‐induced neurogenesis and EE‐induced neurogenesis.

Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation

Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein-1 (MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children.

Resistance to Genotoxic Stresses in Arctica islandica, the Longest Living Noncolonial Animal: Is Extreme Longevity Associated With a Multistress Resistance Phenotype?

Bivalve molluscs are newly discovered models of successful aging. Here, we test the hypothesis that extremely long-lived bivalves are not uniquely resistant to oxidative stressors (eg, tert-butyl hydroperoxide, as demonstrated in previous studies) but exhibit a multistress resistance phenotype. We contrasted resistance (in terms of organismal mortality) to genotoxic stresses (including topoisomerase inhibitors, agents that cross-link DNA or impair genomic integrity through DNA alkylation or methylation) and to mitochondrial oxidative stressors in three bivalve mollusc species with dramatically differing life spans: Arctica islandica (ocean quahog), Mercenaria mercenaria (northern quahog), and the Atlantic bay scallop, Argopecten irradians irradians (maximum species life spans: >500, >100, and ~2 years, respectively). With all stressors, the short-lived A i irradians were significantly less resistant than the two longer lived species. Arctica islandica were consistently more resistant than M mercenaria to mortality induced by oxidative stressors as well as DNA methylating agent nitrogen mustard and the DNA alkylating agent methyl methanesulfonate. The same trend was not observed for genotoxic agents that act through cross-linking DNA. In contrast, M mercenaria tended to be more resistant to epirubicin and genotoxic stressors, which cause DNA damage by inhibiting topoisomerases. To our knowledge, this is the first study comparing resistance to genotoxic stressors in bivalve mollusc species with disparate longevities. In line with previous studies of comparative stress resistance and longevity, our data extends, at least in part, the evidence for the hypothesis that an association exists between longevity and a general resistance to multiplex stressors, not solely oxidative stress. This work also provides justification for further investigation into the interspecies differences in stress response signatures induced by a diverse array of stressors in short-lived and long-lived bivalves, including pharmacological agents that elicit endoplasmic reticulum stress and cellular stress caused by activation of innate immunity.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model

Adult neurogenesis and Alzheimers disease Alzheimers disease (AD) pathology destroys neurons and synapses in the brain, leading to dementia. The brain generates new neurons throughout life in the hippocampus, a process called adult hippocampal neurogenesis (AHN). Choi et al. found that blocking AHN exacerbated cognitive impairment in an AD mouse model (see the Perspective by Spires-Jones and Ritchie). Inducing neurogenesis alone did not improve cognition in AD mice, whereas inducing neurogenesis while simultaneously ameliorating the neuronal environment via exercise did. The use of genetic or pharmacological treatments that simultaneously induced neurogenesis and increased levels of brain-derived neurotrophic factor (BDNF) mimicked the benefits of exercise on cognition. Thus, inducing both neurogenesis and providing BDNF may be useful as an AD therapeutic. Science, this issue p. eaan8821; see also p. 975 Adult neurogenesis plays a critical role in neurodegeneration and cognition in a mouse model of Alzheimer’s disease. INTRODUCTION Alzheimer’s disease (AD) is the most common form of age-related dementia, characterized by cognitive impairment, neurodegeneration, β-amyloid (Aβ) deposition, neurofibrillary tangle formation, and neuroinflammation. The most popular therapeutic approach aimed at reducing Aβ burden has not yet proved effective in halting disease progression. A successful therapy would both remove the pathological hallmarks of the disease and provide some functional recovery. The hippocampus contains neural progenitor cells that continue to generate new neurons, a process called adult hippocampal neurogenesis (AHN). AHN is impaired before the onset of classical AD pathology in AD mouse models. Human AHN has also been reported to be altered in AD patients. However, evidence supporting a role for AHN in AD has remained sparse and inconclusive. RATIONALE Two fundamental questions remain: (i) whether AHN could be enhanced and exploited for therapeutic purposes for AD, and (ii) whether AHN impairment mediates aspects of AD pathogenesis. To address these questions, we increased AHN genetically (WNT3) and pharmacologically (P7C3) in AD transgenic 5×FAD mice and explored whether promoting AHN alone can ameliorate AD pathology and behavioral symptoms. We assessed the role of exercise, a known neurogenic stimulus, and explored whether promoting AHN in conjunction with the salutary biochemical changes induced by exercise can improve AD pathology and behavioral symptoms in mice. We also investigated whether AHN suppression, by irradiation, temozolomide, or dominant-negative WNT, contributes to AD pathogenesis and assessed the functional roles of AHN in AD. RESULTS Inducing AHN alone conferred minimal to no benefit for improving cognition in 5×FAD mice. Exercise-induced AHN improved cognition along with reduced Aβ load and increased levels of brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), fibronectin type III domain–containing protein–5 (FNDC5), and synaptic markers. However, AHN activation was also required for exercise-induced improvement in memory. Inducing AHN genetically and pharmacologically in combination with elevating BDNF levels mimicked beneficial effects of exercise on AD mice. Conversely, suppressing AHN in early stages of AD exacerbated neuronal vulnerability in later stages of AD, leading to cognitive impairment and increased neuronal loss. However, no such effects from AHN ablation were observed in nontransgenic wild-type (WT) mice, suggesting that AHN has a specific role in AD. CONCLUSION Promoting AHN can only ameliorate AD pathology and cognitive deficits in the presence of a healthier, improved local brain environment, e.g., stimulated by exercise. Increasing AHN alone combined with overexpression of BDNF could mimic exercise-induced improvements in cognition, without reducing Aβ burden. Adult-born neurons generated very early in life are critical for maintaining hippocampal neuronal populations in the hostile brain environment created by AD later in life. Thus, AHN impairment may be a primary event that later mediates other aspects of AD pathogenesis. Future attempts to create pharmacological mimetics of the benefits of exercise on both increased AHN and BDNF may someday provide an effective means for improving cognition in AD. Moreover, increasing neurogenesis in the earliest stages of AD pathogenesis may protect against neuronal cell death later in the disease, providing a potentially powerful disease-modifying treatment strategy for AD. Role of adult-born neurons in AD. Inducing AHN alone by WNT3 and P7C3 together did not prevent cognitive dysfunction, whereas activating AHN through exercise improved memory in 5×FAD mice. Increasing AHN alone together with overexpression of BDNF could mimic exercise-induced improvement in cognition. Suppressing AHN exacerbated neuronal vulnerability, leading to cognitive impairment and increased neuronal loss in 5×FAD mice, but not in WT mice. Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.