Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

AbstractOutside of the neurogenic niches of the brain, postmitotic neurons have not been found to undergo efficient regeneration. Here we demonstrate that Purkinje cells (PCs), which are born at midgestation and are crucial for both development and function of cerebellar circuits, are rapidly and fully regenerated following their ablation at birth. New PCs are produced by a previously unidentified progenitor population and support normal cerebellum development. The number of PC progenitors and their regenerative capacity, however, diminish soon after birth, and consequently PCs are poorly replenished when ablated at postnatal day 5. Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell size, but scaling of neuron types is disrupted and cerebellar function is impaired. Our findings thus provide a new paradigm in the field of neuron regeneration by identifying a unipotent neural progenitor that buffers against perinatal brain injury in a stage-dependent process.One sentence summaryInjury induces a dormant progenitor population present at birth to regenerate cerebellar neurons in a time-dependent manner.

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Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

eLife ◽

10.7554/elife.39879 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

N Sumru Bayin ◽

Alexandre Wojcinski ◽

Aurelien Mourton ◽

Hiromitsu Saito ◽

Noboru Suzuki ◽

...

Keyword(s):

Purkinje Neurons ◽

New Paradigm ◽

Perinatal Brain Injury ◽

Cerebellar Function ◽

Efficient Regeneration ◽

Age Dependent ◽

Cerebellum Development ◽

And Function ◽

The Brain ◽

Normal Cerebellum

Outside of the neurogenic niches of the brain, postmitotic neurons have not been found to undergo efficient regeneration. We demonstrate that mouse Purkinje cells (PCs), which are born at midgestation and are crucial for development and function of cerebellar circuits, are rapidly and fully regenerated following their ablation at birth. New PCs are produced from immature FOXP2+ Purkinje cell precursors (iPCs) that are able to enter the cell cycle and support normal cerebellum development. The number of iPCs and their regenerative capacity, however, diminish soon after birth and consequently PCs are poorly replenished when ablated at postnatal day five. Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell size, but scaling of neuron types is disrupted and cerebellar function is impaired. Our findings provide a new paradigm in the field of neuron regeneration by identifying a population of immature neurons that buffers against perinatal brain injury in a stage-dependent process.

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Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

Biochemical Society Transactions ◽

10.1042/bst0381001 ◽

2010 ◽

Vol 38 (4) ◽

pp. 1001-1005 ◽

Cited By ~ 14

Author(s):

Kunie Ando ◽

Karelle Leroy ◽

Céline Heraud ◽

Anna Kabova ◽

Zehra Yilmaz ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Double Mutant ◽

Transgenic Mouse Model ◽

Tau Proteins ◽

Dependent Manner ◽

Age Dependent ◽

Ad Alzheimer’S Disease ◽

Tau Aggregation ◽

The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

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The hypothalamus to brainstem circuit suppresses late-onset body weight gain

Scientific Reports ◽

10.1038/s41598-019-54870-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuko Maejima ◽

Shigeki Kato ◽

Shoichiro Horita ◽

Yoichi Ueta ◽

Seiichi Takenoshita ◽

...

Keyword(s):

Body Weight ◽

Neural Circuits ◽

Late Onset ◽

Body Weight Gain ◽

Growth Period ◽

Underlying Mechanism ◽

Dependent Manner ◽

Aged Rats ◽

Age Dependent ◽

The Brain

AbstractBody weight (BW) is regulated in age-dependent manner; it continues to increase during growth period, and reaches a plateau once reaching adulthood. However, its underlying mechanism remains unknown. Regarding such mechanisms in the brain, we here report that neural circuits from the hypothalamus (paraventricular nucleus: PVN) to the brainstem (dorsal vagal complex: DVC) suppress late-onset BW gain without affecting food intake. The genetic suppression of the PVN-DVC circuit induced BW increase only in aged rats, indicating that this circuit contributes to suppress the BW at a fixed level after reaching adulthood. PVN neurons in the hypothalamus were inactive in younger rats but active in aged rats. The density of neuropeptide Y (NPY) terminal/fiber is reduced in the aged rat PVN area. The differences in neuronal activity, including oxytocin neurons in the PVN, were affected by the application of NPY or its receptor inhibitor, indicating that NPY is a possible regulator of this pathway. Our data provide new insights into understanding age-dependent BW regulation.

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Age-related sex differences in the expression of important disease-linked mitochondrial proteins in mice

Biology of Sex Differences ◽

10.1186/s13293-019-0267-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Michael Moschinger ◽

Karolina E. Hilse ◽

Anne Rupprecht ◽

Ute Zeitz ◽

Reinhold G. Erben ◽

...

Keyword(s):

Protein Expression ◽

Western Blot ◽

Expression Patterns ◽

Mitochondrial Proteins ◽

List Type ◽

Dependent Manner ◽

Age Cohorts ◽

Brown Adipose ◽

Age Dependent ◽

The Brain

Abstract The prevalence and progression of many illnesses, such as neurodegenerative and cardiovascular diseases, obesity, and cancer, vary between women and men, often in an age-dependent manner. A joint hallmark of these diseases is some type of mitochondrial dysfunction. While several mitochondrial proteins are known to be regulated by sex hormones, the levels of those proteins have not been systematically analyzed with regard to sex and age, and studies that consider sex and/or age differences in the protein expression are very rare. In this study, we compared the expression patterns of physiologically important mitochondrial proteins in female and male C57BL/6N mice of age cohorts frequently used in experiments. We found that sex-related differences in the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) occur in an age-dependent manner. The sex-specific expression of UCP1 and UCP3 in brown adipose tissue (BAT) was inversely correlated with differences in body weight. Expression of UCP4 in the brain, Complex I in the spleen, and Complex II in the brain and BAT was least affected by the sex of the mouse. We further demonstrated that there are serious limitations in using VDAC1 and actin as markers in western blot analyses, due to their sex- and age-specific fluctuations. Our results confirm that sex and age are important parameters and should be taken into account by researchers who examine the mechanistic aspects of diseases. Highlights The levels of UCP1 and UCP3 protein expression differ between females and males in an age-dependent manner.Pre-pubertal expression of almost all proteins tested in this study does not depend on the sex of the mouse.Expression of VDAC1 and actin, which are often used as loading control proteins in western blot analysis, is tissue-specifically influenced by sex and age.

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Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

Neural Plasticity ◽

10.1155/2015/167308 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Sylwia Owczarek ◽

Marie Louise Bang ◽

Vladimir Berezin

Keyword(s):

Central Nervous System ◽

Cell Adhesion Molecules ◽

Synaptic Membranes ◽

Dependent Manner ◽

Related Protein ◽

Synaptic Complex ◽

The Central Nervous System ◽

And Function ◽

Activity Dependent ◽

The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

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Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review

Gerontology ◽

10.1159/000478044 ◽

2017 ◽

Vol 64 (1) ◽

pp. 28-35 ◽

Cited By ~ 14

Author(s):

Julie Darrigues ◽

Joost P.M. van Meerwijk ◽

Paola Romagnoli

Keyword(s):

T Lymphocyte ◽

Tissue Repair ◽

Dependent Manner ◽

Peripheral Tissues ◽

Regulatory T Lymphocytes ◽

Age Dependent ◽

And Function ◽

Secondary Lymphoid Organs ◽

Two Populations ◽

Regulatory T Lymphocyte

The generation and function of immuno-suppressive regulatory T lymphocytes (Treg), which can differentiate in the thymus (tTreg) or in the periphery (pTreg), are regulated in an age-dependent manner. tTreg are produced at high levels in the first weeks of age, when they expand and colonize secondary lymphoid organs and peripheral tissues to protect the organism from autoimmune diseases and to promote tissue repair. Once this population of Treg is operational in the periphery, at puberty, thymic output of Treg declines, but self-reactive tTreg generated early on in life are maintained over time and play a major role in preserving homeostasis of the immune system. Extra-thymic pTreg differentiation declines later on in life. pTreg generated throughout life mainly protect the organism from chronic inflammation and the semi-allogeneic fetus from rejection. In this review, age-dependent modulation of the production and function of these two populations of Treg is described.

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A LRRK2/dLRRK-mediated lysosomal pathway that contributes to glial cell death and DA neuron survival

10.1101/2021.11.25.469972 ◽

2021 ◽

Author(s):

Linfang Wang ◽

Honglei Wang ◽

Margaret S Ho

Keyword(s):

Caspase 3 ◽

Kinase Activity ◽

Dependent Manner ◽

Dopaminergic Neurodegeneration ◽

Age Dependent ◽

Sporadic Parkinson’S Disease ◽

Locomotor Deficits ◽

And Function ◽

Reduced Activity

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). A plethora of evidence has indicated a role for LRRK2 in endolysosomal trafficking in neurons, while LRRK2 function in glia, although highly expressed, remains largely unknown. Here we present evidence that LRRK2/dLRRK mediates a glial lysosomal pathway that contributes to the mechanism of PD. Independent of its kinase activity, glial LRRK2/dLRRK knockdown in the immortalized microglial cells or flies results in enlarged and swelling lysosomes fewer in number. These lysosomes are less mobile, wrongly acidified, and exhibit defective membrane permeability and reduced activity of the lysosome hydrolase cathespin B. In addition, microglial LRRK2 depletion causes increased Caspase 3 levels, leading to glial apoptosis, dopaminergic neurodegeneration, and locomotor deficits in an age-dependent manner. Taken together, these findings demonstrate a functional role of LRRK2/dLRRK in regulating the glial lysosomal pathway; deficits in lysosomal biogenesis and function linking to glial apoptosis potentially underlie the mechanism of DA neurodegeneration, contributing to the progression of PD.

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Antioxidant radiation response of rat brain after exposure to a clinical dose of γ-rays

Archives of Biological Sciences ◽

10.2298/abs0504273t ◽

2005 ◽

Vol 57 (4) ◽

pp. 273-275

Author(s):

Ana Todorovic ◽

Jelena Kasapovic ◽

Snezana Pejic ◽

Vesna Stojiljkovic ◽

Snezana Pajovic

Keyword(s):

Superoxide Dismutase ◽

Cell Structure ◽

Brain Regions ◽

Dependent Manner ◽

Clinical Dose ◽

Mitochondrial Superoxide ◽

Γ Rays ◽

And Function ◽

The Brain ◽

Mitochondrial Superoxide Dismutase

Ionizing radiation increases intracellular production of reactive oxygen species (ros), which can damage cell structure and function. The brain is particularly vulnerable to oxidative injury, and in an area-dependent manner. In order to elucidate differences in enzymatic antioxidative responses of the rat hippocampus and cortex, we measured the activities of cytosol superoxide dismutase (CuZnSOD), mitochondrial superoxide dismutase (MnSOD), and catalase (CAT) in those two brain regions, isolated 1 h and 24 h after exposure to 2 Gy of ?-rays. Our results indicate that the lower MnSOD activity and inducibility found in the hippocampus are probably among the main reasons for particularly great oxidative vulnerability of this brain region.

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CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer’s disease

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0084 ◽

2018 ◽

Vol 29 (8) ◽

pp. 837-848 ◽

Cited By ~ 8

Author(s):

Lihang Zhang ◽

Juan Xu ◽

Jinchao Gao ◽

Yuncheng Wu ◽

Ming Yin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Dependent Manner ◽

Independent Manner ◽

Physiological Conditions ◽

The Central Nervous System ◽

And Function ◽

Cluster Of Differentiation ◽

The Brain

Abstract Neurons and microglia are two major components in the central nervous system (CNS). The interactions between them play important roles in maintaining homeostasis of the brain. In recent years, substantial studies have focused on the interactions between neurons and microglia, revealing that microglia become reactive when the interactions are pathophysiologically interfered, usually accompanying neuronal injury, which is a common feature for Alzheimer’s disease (AD). Many molecules and factors participate in these physiological and pathological processes, either in a contact-dependent or a contact-independent manner. Accumulating studies have revealed that in the CNS, cluster of differentiation-200 (CD200) and fractalkine (CX3CL1) expressed mainly on neurons and triggering receptor expressed on myeloid cells 2 (TREM2) expressed mainly on microglia. These molecules can mediate neuron-microglia interactions in a contact-dependent manner and contribute to the pathogenesis of AD. Here, we review the expression, distribution, and function of CD200, CX3CL1, and TREM2 in regulating neuron-microglia interactions under physiological conditions as well as in AD.

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