Differential Sorting of Nerve Growth Factor and Brain-Derived Neurotrophic Factor in Hippocampal Neurons

Mowla, Seyed Javad; Pareek, Sangeeta; Farhadi, H. Francis; Petrecca, Kevin; Fawcett, James P.; Seidah, Nabil G.; Morris, Stephen; Sossin, Wayne S.; Murphy, Richard A.

doi:10.1523/jneurosci.19-06-02069.1999

Cited by 300 publications

(259 citation statements)

References 54 publications

(72 reference statements)

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“…36 The entorhinal cortex is the earliest cortical region affected by AD (stages I/II), followed by the hippocampus (stages III/IV). 20 In our study we observed a clear augmentation in the levels of nonenzymatic oxidative modifications in pro-NGF molecules in hippocampus and entorhinal cortex samples from AD-affected brains. This increase is present for both lipoxidation and glycoxidation.…”

Section: Discussionsupporting

confidence: 55%

Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

Kichev

Ilieva

Piñol‐Ripoll

et al. 2009

The American Journal of Pathology

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Pro-nerve growth factor (pro-NGF) is expressed at increased levels in Alzheimer's disease (AD)-affected brains and is able to induce cell death in cultures; however, the reasons for these phenomena remain elusive. Here we show that pro-NGF in human ADaffected hippocampus and entorhinal cortex is modified by advanced glycation and lipoxidation end-products in a stage-dependent manner. These modifications block pro-NGF processing to mature NGF, thus making the proneurotrophin especially effective in inducing apoptosis of PC12 cells in culture through the p75 neurotrophin receptor. The processing of advanced glycation and lipoxidation end-products in vitro modified recombinant human pro-NGF is severely impaired , as evidenced by Western blot and by examining its physiological functionality in cell cultures. We also report that modified recombinant human pro-NGF , as well as pro-NGF isolated from human brain affected by AD , cause impairment of learning tasks when administered intracerebroventricularly in mice , which correlates with AD-associated learning impairment. Taken together , the data we present here offer a novel pathway of ethiopathogenesis in AD caused by advanced glycation and lipoxidation end-products modification of pro-NGF. Oxidative stress occurs early in the progression of Alzheimer's disease (AD) even before the development of the pathological hallmarks, neurofibrillary tangles and senile plaques, depending on the stage of the disease and cerebral region. This is accompanied by degeneration of synapses and dendrites, and by cell death and neuronal loss.

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Section: Discussionsupporting

confidence: 55%

Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

Kichev

Ilieva

Piñol‐Ripoll

et al. 2009

The American Journal of Pathology

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“…These apparent discrepancies in the time course of BDNF secretion could reflect differences in the sorting and release of native BDNF, AdVBDNF, and BDNF-GFP (cf. Fawcett et al, 1997; Mowla et al, 1999) or other differences among the models used in these three studies.…”

Section: Discussionmentioning

confidence: 97%

Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons

2002

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Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent modifications of neuronal connectivity and synaptic strength, including establishment of hippocampal long-term potentiation (LTP). To shed light on mechanisms underlying BDNF-dependent synaptic plasticity, the present study was undertaken to characterize release of native BDNF from newborn rat hippocampal neurons in response to physiologically relevant patterns of electrical field stimulation in culture, including tonic stimulation at 5 Hz, bursting stimulation at 25 and 100 Hz, and theta-burst stimulation (TBS). Release was measured using the ELISA in situ technique, developed in our laboratory to quantify secretion of native BDNF without the need to first overexpress the protein to nonphysiological levels. Each stimulation protocol resulted in a significant increase in BDNF release that was tetrodotoxin sensitive and occurred in the absence of glutamate receptor activation. However, 100 Hz tetanus and TBS, stimulus patterns that are most effective in inducing hippocampal LTP, were significantly more effective in releasing native BDNF than lower-frequency stimulation. For all stimulation protocols tested, removal of extracellular calcium, or blockade of N-type calcium channels, prevented BDNF release. Similarly, depletion of intracellular calcium stores with thapsigargin and treatment with dantrolene, an inhibitor of calcium release from caffeine-ryanodine-sensitive stores, markedly inhibited activity-dependent BDNF release. Our results indicate that BDNF release can encode temporal features of hippocampal neuronal activity. The dual requirement for calcium influx through N-type calcium channels and calcium mobilization from intracellular stores strongly implicates a role for calcium-induced calcium release in activity-dependent BDNF secretion.

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“…Synthesized as a precursor, proBDNF is then sorted into one of the two secretory pathways: constitutive (passive) or regulated (induced or active) (4)(5)(6). Until recently, only mature BDNF (mBDNF) was considered biologically active.…”

mentioning

confidence: 99%

Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

Nagappan

Zaitsev

Senatorov

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

242

185

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Pro-and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by highfrequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect proBDNF or mBDNF, we show that low-frequency stimulation induced predominant proBDNF secretion in cultured hippocampal neurons. In contrast, high-frequency stimulation preferentially increased extracellular mBDNF. Inhibition of extracellular, but not intracellular cleavage of proBDNF greatly reduced high-frequency stimulationinduced extracellular mBDNF. Moreover, high-frequency, but not low-frequency stimulation selectively induced the secretion of tissue plasminogen activator, a key protease involved in extracellular proBDNF to mBDNF conversion. Thus, high-frequency neuronal activity controls the ratio of extracellular proBDNF/mBDNF by regulating the secretion of extracellular proteases. Our study demonstrates activity-dependent control of extracellular proteolytic cleavage of a secretory protein, and reveals an important mechanism that controls diametrically opposed functions of BDNF isoforms.BDNF ͉ hippocampus ͉ LTP ͉ proteases ͉ tPA B rain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent processes, such as synapse development and plasticity (1-3). Synthesized as a precursor, proBDNF is then sorted into one of the two secretory pathways: constitutive (passive) or regulated (induced or active) (4-6). Until recently, only mature BDNF (mBDNF) was considered biologically active. This view was challenged by findings that exogenous proBDNF induces apoptosis in peripheral neurons (7) and facilitates long-term depression (LTD) in the hippocampus (8). ProBDNF, is believed to be cleaved intracellularly by furin in trans-Golgi or by pro-protein convertase 1/3 (PC1/3) in secretory granules (9, 10) to generate mBDNF. Recently, Lee et al. demonstrated that proBDNF could be converted to mBDNF by extracellular proteases, such as plasmin and matrixmetalloprotease-7 (11). The physiological significance of extracellular proBDNF cleavage became evident when proBDNF 3 mBDNF conversion through the tissue plasminogen activator (tPA)/plasminogen cascade was shown to be essential for late phase long-term potentiation (L-LTP) in the hippocampus (12). Given the opposing biological effects of proBDNF and mBDNF, mechanisms controlling the cleavage of proBDNF have emerged as important mechanisms in controlling the direction of BDNF regulation (13).Neuronal release of endogenous proBDNF remains controversial. While studies using neuronal cultures in absence of glial cells and in the presence of cell impermeant ␣2 antiplasmin inhibitors successfully detected proBDNF in the extracellular culture medium (7), a recent study by Mat...

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Differential Sorting of Nerve Growth Factor and Brain-Derived Neurotrophic Factor in Hippocampal Neurons

Cited by 300 publications

References 54 publications

Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons

Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

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