Neurological dysfunctions associated with altered <scp>BACE</scp>1‐dependent Neuregulin‐1 signaling

Hu, Xiangyou; Fan, Qingyuan; Hou, Hailong; Yan, Riqiang

doi:10.1111/jnc.13395

Cited by 45 publications

(42 citation statements)

References 230 publications

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“…To identify which neuronal protease may mediate DR6 shedding, neuronal cultures were used. The partial DR6 cleavage by ADAM10 behaves similar to other ADAM10 substrates, such as APP, which are also partly cleaved by ADAM10 and partly by other proteases, including the b-secretase BACE1 (Hu et al, 2016;Kuhn et al, 2016). While membranetype 1 matrix metalloprotease (MT1-MMP) was suggested as a DR6 protease in tumor cells (Tam et al, 2004;DeRosa et al, 2008), lentiviral knockdown of MT1-MMP did not alter DR6 shedding in neurons ( Fig EV1).…”

Section: Resultsmentioning

confidence: 66%

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

et al. 2018

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Death receptor 6 (DR6) is an orphan member of the TNF receptor superfamily and controls cell death and differentiation in a cell-autonomous manner in different cell types. Here, we report an additional non-cell-autonomous function for DR6 in the peripheral nervous system (PNS). DR6-knockout (DR6 KO) mice showed precocious myelination in the PNS Using an myelination assay, we demonstrate that neuronal DR6 acts in on Schwann cells (SCs) and reduces SC proliferation and myelination independently of its cytoplasmic death domain. Mechanistically, DR6 was found to be cleaved in neurons by "a disintegrin and metalloprotease 10" (ADAM10), releasing the soluble DR6 ectodomain (sDR6). Notably, in the myelination assay, sDR6 was sufficient to rescue the DR6 KO phenotype. Thus, in addition to the cell-autonomous receptor function of full-length DR6, the proteolytically released sDR6 can unexpectedly also act as a paracrine signaling factor in the PNS in a non-cell-autonomous manner during SC proliferation and myelination. This new mode of DR6 signaling will be relevant in future attempts to target DR6 in disease settings.

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Section: Resultsmentioning

confidence: 66%

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

et al. 2018

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“…It is suggested that these phenotypes are partly attributed to neuregulin-1 (Nrg1) signaling, which is known to regulate various brain functions through its actions on glutamatergic, GABAergic, and dopaminergic synapses [see updated review in (Mei and Nave, 2014) for more detailed discussion on the role of Nrg1 in synaptic function]. BACE1-dependent Nrg1 signaling is required for normal myelination during development, remyelination after injury, and maintenance of muscle spindles [see recent review by (Fleck et al, 2012; Hu et al, 2015)]. Impaired neuronal migration is due to abrogated cleavage of Sema3A-mediated CHL1 cleavage by BACE1 (Barao et al, 2015; Hitt et al, 2012; Kuhn et al, 2012; Zhou et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Yan

Fan

Zhou

et al. 2016

Neuroscience & Biobehavioral Reviews

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Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer’s disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

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“…Physiological concentrations of Aβ (in pM range) have been shown to facilitate synaptic plasticity [65] and BACE1 deficiency will cause a remarkable reduction in Aβ. Such a loss of physiological levels of Aβ may also lead to synaptic deficits.BACE1 deficiency alters synaptic plasticity in relation to neuregulin-1 cleavage: An alternative possibility is that the synaptic dysfunctions in BACE1-null mice may arise from abnormal processing of substrates other than APP, i.e., neuregulin-1 (Nrg1) [66–68]. Nrg1 has a plethora of functions in the central and peripheral nervous systems, which include regulation of myelination, radial and tangential neuronal migration of glutamatergic and GABAergic neurons, and synaptic plasticity [69].…”

Section: Effects Of Bace1 On Synaptic Functionsmentioning

confidence: 99%

Role of BACE1 in Alzheimer’s synaptic function

Das

Yan

2017

Transl Neurodegener

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100

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Alzheimer’s disease (AD) is the most common age-dependent disease of dementia, and there is currently no cure available. This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles. Although the exact etiology of AD remains a mystery, studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides (Aβ) is likely to be a predominant early event in AD pathological development. Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1). Chemical inhibition of BACE1 has been shown to reduce Aβ in animal studies and in human trials. While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients, it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients. This review summarizes the recent studies on BACE1 synaptic functions. This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.

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Neurological dysfunctions associated with altered BACE1‐dependent Neuregulin‐1 signaling

Cited by 45 publications

References 230 publications

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Role of BACE1 in Alzheimer’s synaptic function

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