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Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.

ABSTRACT: Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.

SUBMITTER: Velanac V

PROVIDER: S-EPMC3267053 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.

Velanac Viktorija V Unterbarnscheidt Tilmann T Hinrichs Wilko W Gummert Maike N MN Fischer Tobias M TM Rossner Moritz J MJ Trimarco Amelia A Brivio Veronica V Taveggia Carla C Willem Michael M Haass Christian C Möbius Wiebke W Nave Klaus-Armin KA Schwab Markus H MH

Glia 20111102 2

Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination ...[more]

PMID: 22052506

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Project description:BACKGROUND:The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer's disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients. METHODS:This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for A?1-42, A?1-40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1. RESULTS:Levels of NRG1 were significantly increased in the CSF of AD (+?36%) and MCI-AD (+?28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with A?1-42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p?=?0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin. CONCLUSIONS:Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD.

Project description:OBJECTIVE:Functional electrical stimulation (FES) is a promising technology for restoring movement to paralyzed limbs. Intracortical brain-computer interfaces (iBCIs) have enabled intuitive control over virtual and robotic movements, and more recently over upper extremity FES neuroprostheses. However, electrical stimulation of muscles creates artifacts in intracortical microelectrode recordings that could degrade iBCI performance. Here, we investigate methods for reducing the cortically recorded artifacts that result from peripheral electrical stimulation. APPROACH:One participant in the BrainGate2 pilot clinical trial had two intracortical microelectrode arrays placed in the motor cortex, and thirty-six stimulating intramuscular electrodes placed in the muscles of the contralateral limb. We characterized intracortically recorded electrical artifacts during both intramuscular and surface stimulation. We compared the performance of three artifact reduction methods: blanking, common average reference (CAR) and linear regression reference (LRR), which creates channel-specific reference signals, composed of weighted sums of other channels. MAIN RESULTS:Electrical artifacts resulting from surface stimulation were 175??×??larger than baseline neural recordings (which were 110 µV peak-to-peak), while intramuscular stimulation artifacts were only 4??×??larger. The artifact waveforms were highly consistent across electrodes within each array. Application of LRR reduced artifact magnitudes to less than 10 µV and largely preserved the original neural feature values used for decoding. Unmitigated stimulation artifacts decreased iBCI decoding performance, but performance was almost completely recovered using LRR, which outperformed CAR and blanking and extracted useful neural information during stimulation artifact periods. SIGNIFICANCE:The LRR method was effective at reducing electrical artifacts resulting from both intramuscular and surface FES, and almost completely restored iBCI decoding performance (>90% recovery for surface stimulation and full recovery for intramuscular stimulation). The results demonstrate that FES-induced artifacts can be easily mitigated in FES??+??iBCI systems by using LRR for artifact reduction, and suggest that the LRR method may also be useful in other noise reduction applications.

Dataset Information

Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.

Publications

Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.

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