34 research outputs found
The systemic environment: at the interface of aging and adult neurogenesis.
Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms
Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation
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Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain.
Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation
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A maternal brain hormone that builds bone
In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals
Platelets Give a Running Start to Adult Hippocampal Neurogenesis
Exercise boosts neural stem and progenitor cell proliferation and differentiation in the dentate gyrus region of the hippocampus. In this issue of Stem Cell Reports, Leiter et al. (2019) identify acute exercise-induced platelet activation and platelet factor-4 as novel systemic mediators of adult hippocampal neurogenesis. : Exercise boosts neural stem and progenitor cell proliferation and differentiation in the dentate gyrus region of the hippocampus. In this issue of Stem Cell Reports, Leiter et al. (2019) identify acute exercise-induced platelet activation and platelet factor-4 as novel systemic mediators of adult hippocampal neurogenesis
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The systemic environment: at the interface of aging and adult neurogenesis.
Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms
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Innovative approaches in cognitive aging
Novel approaches to address cognitive aging and to delay or prevent cognitive decline in older individuals will require a better understanding of the biological and environmental factors that contribute to it. Studies in animal models-in particular, animals whose cognitive trajectory across their life span closely tracks that of humans-can provide important insights into the factors that contribute to the accumulation of reserve and ways in which it is preserved or depleted. A better understanding of the molecular processes that underlie these elements would enhance and guide not only research but also treatment approaches to these issues. These treatment approaches may include noninvasive brain stimulation and drug treatments to promote youthfulness or combat the aging process. It is important to realize, however, that these processes occur in the context of the human experience, and studies of them must consider the complexity and individuality of each person's life
Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration
Abstract Background Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer’s disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo. Methods Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus. Results We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo. Conclusions Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration
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Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation