Increasing evidence suggests that synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease. Understanding the role of brain-derived neurotrophic factor (BDNF) in synaptic plasticity and synaptogenesis, the impact of the BDNF Val66Met polymorphism in Alzheimer's disease-relevant endophenotypes - including episodic memory and hippocampal volume - and the technological progress in measuring synaptic changes in humans all pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis. This article reviews the key issues in translating BDNF biology into synaptic repair therapies.

Pro–brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and TrkB.

Among all neurotrophins, brain-derived neurotrophic factor (BDNF) stands out for its high level of expression in the brain and its potent effects on synapses. It is now widely accepted that the main function of BDNF in the adult brain is to regulate synapses, with structural and functional effects ranging from short-term to long-lasting, on excitatory or inhibitory synapses, in many brain regions. The diverse effects of BDNF on brain synapses stem from its complex downstream signaling cascades, as well as the diametrically opposing effects of the pro- and mature form through distinct receptors, TrkB and p75(NTR). Many aspects of BDNF cell biology are regulated by neuronal activity. The synergistic interactions between neuronal activity and synaptic plasticity by BDNF make it an ideal and essential regulator of cellular processes that underlie cognition and other complex behaviors. Indeed, numerous studies firmly established that BDNF plays a critical role in hippocampal long-term potentiation (LTP), a long-term enhancement of synaptic efficacy thought to underlie learning and memory. Converging evidence now strongly suggest that deficits in BDNF signaling contribute to the pathogenesis of several major diseases and disorders such as Huntington's disease, Alzheimer's disease, and depression. Thus, manipulating BDNF pathways represents a viable treatment approach to a variety of neurological and psychiatric disorders.

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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...

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.

Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activitydependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNFp75 NTR signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination. neuromuscular junction | pro-neurotrophin | synapse competition

Postsynaptic cells generate positive and negative signals that retrogradely modulate presynaptic function. At developing neuromuscular synapses, prolonged stimulation of muscle cells induces sustained synaptic depression. We provide evidence that pro–brain-derived neurotrophic factor (BDNF) is a negative retrograde signal that can be converted into a positive signal by metalloproteases at the synaptic junctions. Application of pro-BDNF induces a dramatic decrease in synaptic efficacy followed by a retraction of presynaptic terminals, and these effects are mediated by presynaptic pan-neurotrophin receptor p75 (p75NTR), the pro-BDNF receptor. A brief stimulation of myocytes expressing cleavable or uncleavable pro-BDNF elicits synaptic potentiation or depression, respectively. Extracellular application of metalloprotease inhibitors, which inhibits the cleavage of endogenous pro-BDNF, facilitates the muscle stimulation–induced synaptic depression. Inhibition of presynaptic p75NTR or postsynaptic BDNF expression also blocks the activity-dependent synaptic depression and retraction. These results support a model in which postsynaptic secretion of a single molecule, pro-BDNF, may stabilize or eliminate presynaptic terminals depending on its proteolytic conversion at the synapses.