Hippocampal epigenetic modification at the doublecortin gene is involved in the impairment of neurogenesis with aging

Kuzumaki, Naoko; Ikegami, Daigo; Tamura, Rie; Sasaki, Takuya; Niikura, Keiichi; Narita, Michiko; Miyashita, Kazuhiko; Imai, Shoichi; Takeshima, Hideyuki; Ando, Takayuki; Igarashi, Katsuhide; Kanno, Jun; Ushijima, Toshikazu; Suzuki, Tsutomu; Narita, Minoru

doi:10.1002/syn.20768

Cited by 40 publications

(15 citation statements)

References 18 publications

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“…These modifiable environmental interventions increase brain and serum BDNF levels[43]–[46]. Aerobic exercise for example induces both short-term and longer-term increases in circulating BDNF levels, in parallel with improvements in memory performance[47].…”

Section: Discussionmentioning

confidence: 99%

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

et al. 2010

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During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.

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Section: Discussionmentioning

confidence: 99%

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

et al. 2010

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“…Decreased hippocampal neurogenesis is proposed as an important mechanism underlying age‐related cognitive decline as well as neurodegenerative disorders such as AD and various types of dementia (Kuzumaki et al, ). Evidence in this regard was recently published in two separate recent studies examining hippocampal neurogenesis in human tissue from people suffering mild cognitive impairment and AD.…”

Section: Hippocampal Neurogenesis During the Developmentally Criticalmentioning

confidence: 99%

Born this way: Hippocampal neurogenesis across the lifespan

2019

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The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis‐permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease‐related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit.

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“…Increasing evidence has shown that epigenetic mechanisms are involved in regulating aging-related cellular behaviors. 29,30 It is proposed that the epigenetic modulated switch of microglia polarization is influenced by aging. Indeed, by comparing the mRNA levels of those markers and related molecules in aged mice (16-18 months old) with young mice (2-3 months old), we showed that the M1 markers such as iNOS, TNF-a and IL-6 were generally increased in aged mice, whereas the M2 markers including Arginase1, CD206 and IGF-I were expressed at lower levels (Figures 7a and b).…”

Section: Da Neurons In the Sncmentioning

confidence: 99%

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

et al. 2013

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Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

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Hippocampal epigenetic modification at the doublecortin gene is involved in the impairment of neurogenesis with aging

Cited by 40 publications

References 18 publications

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

Born this way: Hippocampal neurogenesis across the lifespan

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

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