BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met

Mizui, Toshiyuki; Ishikawa, Yasuyuki; Kumanogoh, Haruko; Lume, Maria; Matsumoto, Tomoya; Hara, Tomoko; Yamawaki, Shigeto; Takahashi, Masami; Shiosaka, Sadao; Itami, Chiaki; Uegaki, Koichi; Saarma, Märt; Kojima, Masami

doi:10.1073/pnas.1422336112

Cited by 110 publications

(127 citation statements)

References 45 publications

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“…In the present study, we showed that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal LTD and this inhibition was not rescued by treatment with a REX p75 NTR antagonist. Recently, we reported that the BDNF pro-peptide facilitates hippocampal LTD, and this enhancement requires p75 NTR , while BDNF successfully rescued hippocampal LTD [15]. Taken together with our recent report [15], the electrophysiological data shown in Figure 3 raise a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability.…”

Section: Discussionsupporting

confidence: 70%

“…Recently, we reported that the BDNF pro-peptide facilitates hippocampal LTD, and this enhancement requires p75 NTR , while BDNF successfully rescued hippocampal LTD [15]. Taken together with our recent report [15], the electrophysiological data shown in Figure 3 raise a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. When present and functioning independently, both proteins (BDNF and its pro-peptide) could engage in their own separate biological activities.…”

Section: Discussionsupporting

confidence: 70%

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BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

Uegaki

Kumanogoh

Mizui

et al. 2017

IJMS

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Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 70%

BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

Uegaki

Kumanogoh

Mizui

et al. 2017

IJMS

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“…Sortilin, another Vps10p receptor, is responsible for intracellular trafficking of newly synthesized proBDNF via its physical interaction with the region of BDNF pro-domain in which the Val66Met substitution resides [34]. BDNF Val66Met has been associated with risk for AD [35] and AD-related intermediate phenotypes [36], albeit inconsistently, and is thought to be an important factor in modulating neuroplasciticty [10]. Our results may provide insight into the inconsistent literature on the effects of BDNF Val66Met (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, it was recently shown that BDNF administration in iPSC-derived neuron cultures up-regulates SORL1 expression in a SORL1 -genotype dependent manner [8]. The BDNF Val66Met polymorphism determines the activity-dependent secretion of BDNF [9] and also the function of the BDNF pro-peptide in facilitating neuroplasticity (LTD) [10]. As such, BDNF Val66Met may serve as a functional assay for BDNF activity in the brain.…”

Section: Introductionmentioning

confidence: 99%

Genetic epistasis regulates amyloid deposition in resilient aging

Felsky

Chibnik

et al. 2017

Alzheimer's & Dementia

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INTRODUCTION The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer’s disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF’s ability to reduce Aβ in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. METHODS We analyzed postmortem brain RNA-sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project, and molecular and structural neuroimaging data for 1 285 subjects from the Alzheimer’s Disease Neuroimaging Initiative. RESULTS We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD, and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [18F]Florbetapir PET. DISCUSSION Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.

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“…These mechanisms include activity-dependent effects on BDNF mRNA abundance and protein synthesis [32], secretion of BDNF from neurons [33], BDNF transcript and protein breakdown [32], post-translational modification from pro- to mature forms of BDNF [34], gene polymorphisms [35], epigenetic modifications [36] subcellular compartmentalization [37], interactions between BDNF signaling and other signaling pathways [38, 39]. Another mechanism can now be added to this list: down-regulation of BDNF mRNA by antidromic firing.…”

Section: Discussionmentioning

confidence: 99%

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus

Bukalo

Lee

Fields

2016

Neuroscience Letters

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Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of APLTD and the cellular mechanisms of memory consolidation.

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BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met

Cited by 110 publications

References 45 publications

BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

Genetic epistasis regulates amyloid deposition in resilient aging

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus

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