Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival

Koshimizu, Hisatsugu; Kiyosue, Kazuyuki; Hara, Tomoko; Hazama, Shunsuke; Suzuki, Shingo; Uegaki, Koichi; Nagappan, Guhan; Zaitsev, Eugene; Hirokawa, Takatsugu; Tatsu, Yoshiro; Ogura, Akihiko; Lu, Bai; Kojima, Masami

doi:10.1186/1756-6606-2-27

Cited by 168 publications

(164 citation statements)

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“…ProBDNF can also inhibit neurite outgrowth and reduce spine density (Koshimizu et al 2009). In contrast, mBDNF activates the high affinity receptor, TrkB, which promotes neuronal survival and synaptic plasticity (Poo 2001).…”

Section: Bdnf and Normal Agingmentioning

confidence: 99%

“…Reduction in levels of proBDNF without a change in mBDNF could reflect increased cleavage of proBDNF as a compensatory response to preserve levels of mBDNF that promote neuronal survival and maintenance of the dendritic tree and axon (Gorski et al 2003;Matsunaga et al 2004). In contrast, proBDNF signals through the p75 NGFR and leads to neurite retraction and loss of spines (Koshimizu et al 2009), so reduced levels of proBDNF would reduce this deleterious effect. These opposite actions of the mature and pro forms of BDNF make it essential to identify the post-translational status of each form in the aging brain as total BDNF expression cannot differentiate between the state of the protein and the differences between the two signaling pathways.…”

Section: Bdnf and Normal Agingmentioning

confidence: 99%

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Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

2018

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Mammalian aging is associated with decline in cognitive functions. Studies searching for a cause of cognitive aging initially focused on neuronal loss but quantitative investigations of rat, monkey, and human brain using stereology demonstrated that in normal aging, unlike in neurodegenerative disease, neurons are not lost. Instead, electron microscopic and MRI studies in normal aging monkeys revealed age-related damage to myelin sheaths, loss of axons, and reduction in white matter volume which correlates with cognitive impairments. However, little is known about the cause of myelin defects or associated axon loss. The present study investigates the effect of age on signaling pathways between oligodendroglia and neurons using a custom PCR array to assess the expression of 87 genes of interest in cortical gray matter and white matter from the inferior parietal lobe (IPL) of normal rhesus monkeys ranging in age from 4.2 to 30.4 years old. From this array data, five target genes of interest were selected for further analysis to confirm gene expression and measure protein expression. The most interesting target gene identified is brain-derived neurotrophic factor (BDNF), which was the only gene that was altered at both mRNA and protein levels. In gray matter, BDNF mRNA was decreased. While the level of the mature form of the protein was unchanged, there was a specific decrease in the precursor form of BDNF. These alterations in the BDNF in gray matter could contribute to the vulnerability and loss of the axons with age.

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Section: Bdnf and Normal Agingmentioning

confidence: 99%

Section: Bdnf and Normal Agingmentioning

confidence: 99%

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

2018

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“…According to the "Ying and Yang" hypothesis (Lu et al, 2005), both mBDNF and proBDNF have particular neurobiological properties. In particular, proBDNF regulate neuronal survival Koshimizu et al, 2009;Woo et al, 2005) and boosts synaptic pruning whereas mBDNF improves the differentiation of new neurons. Also, the conversion of proBDNF into mBDNF seems to be decisive for signal transmission and synaptic plasticity.…”

Section: The Role Of Probdnf In Patients With Schizophreniamentioning

confidence: 99%

“…Recent findings have established that mature and pro-BDNF elicit opposite biological functions Woo et al, 2005), leading to the hypothesis t h a t f r o m a n i n c o r r e c t b a l a n c i n g o f t h e d i verse isoforms may origin a pathological consequence. In recent times, Koshimizu et al (2009) pointed out that overexpression of pro-BDNF leads to apoptosis of cultured cerebellar granule neurons and produce a striking decrease in the number of cholinergic fibers of basal forebrain neurons and hippocampal dendritic spines, without disturbing the survival of these neurons. Blockade of activation of p75 receptor did not permit spine number to fall.…”

Section: The Role Of Probdnf In Patients With Schizophreniamentioning

confidence: 99%

State of Art of Serum Brain-Derived Neurotrophic Factor in Schizophrenia

Carlino¹,

Baiano²,

Vanna³

et al. 2011

Psychiatric Disorders - Trends and Developments

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“…proBDNF is a precursor form of BDNF. It was reported that the signaling of BDNF/TrkB and proBDNF/p75NTR promote neuronal survival and death, respectively [67,68]. There are reports showing that proBDNF may play a role in synaptic depression through p75NTR.…”

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confidence: 99%

BDNF and Synaptic Plasticity: The Recent Cell Biology for Understanding of Brain Disorders

Mizui¹

2013

Clinic Pharmacol Biopharmaceut

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IntroductionThe brain exerts considerable structural and functional plasticity [1][2][3]. As an important interface between neurons, synapses are required for computation of circuits and information processing. Accumulating evidence indicates that once formed, synapses and dendrites can be maintained for long periods of time. However, they are eliminated or rewired to respond to environmental changes, as reported by Walsh and Lichtman (2003) [4]. The cell biology of neurons has been developed to the understanding of pathological mechanisms of brain disorders. This review article will pay an attention to the biological and pathological role of BDNF, which modulate synaptic plasticity in adult brain because this knowledge could prove beneficial for the development of new therapies against brain diseases. Dendritic spines are actin-rich structures, which are part of most excitatory synapses in the central nervous systems. Recent studies have shown that the morphological plasticity of the spine plays a crucial role in higher brain functions, such as learning and memory. This review focuses on recent advances in the research of dendrite spines, synaptic plasticity, and BDNF. Lastly, we will introduce recent reports demonstrating the role of BDNF in depression. Dendrite SpinesThe majority of excitatory synapses develop small protrusions on dendrites, called dendrite spines, which form the main platforms of synaptic input for neurons. Neurotransmitter receptors are largely localized at the surface of spines to counteract the presynaptic structure, axon terminals. Previously, consensus was that spine morphology is controlled for higher brain functions, such as learning and memory. Indeed, this notion has been supported by a significant number of studies. The strength of synaptic activity is controlled by the size and number of dendritic spines [5,6]. Activity-dependent remodeling and stability of spine structures is an important cellular mechanism for the maintenance and refinement of neuronal circuits [7,8]. Developing brain spines are structurally dynamic. Conversely, stable spines predominate during adult stages [2]. Interestingly, imaging studies demonstrate experience-dependent structural alterations of spines in animals [6,8], and spine genesis has a salient association with human cognitive function [9]. Moreover, autopsy studies of patients with dementia indicated a correlation between brain dysfunction and abnormal spine morphology [10,11]. Although synaptic function cannot be assessed from spine morphology, the regulatory mechanisms of spine morphogenesis, and the dynamics of spine morphology would provide insight into higher brain functions and their disorders.Dendritic spines are actin-rich protrusions [12,13] and highly dynamic [14]. The dynamics are controlled by the architecture of their actin cytoskeleton [15]. The formation, maturation, and plasticity of spines depend on actin cytoskeleton remodeling [16,17]. Many of the key molecules controlling this process are members of the Rhofamily of small GTPases...

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Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival

Abstract: Background: Proneurotrophins and mature neurotrophins elicit opposite effects via the p75 neurotrophin receptor (p75 NTR ) and Trk tyrosine kinase receptors, respectively; however the molecular roles of proneurotrophins in the CNS are not fully understood.

Cited by 168 publications

References 58 publications

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

State of Art of Serum Brain-Derived Neurotrophic Factor in Schizophrenia

BDNF and Synaptic Plasticity: The Recent Cell Biology for Understanding of Brain Disorders

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