BACE1 in central nervous system myelination revisited

Treiber, Hannes; Hagemeyer, Nora; Ehrenreich, Hannelore; Simons, Mika

doi:10.1038/mp.2011.140

Cited by 17 publications

(18 citation statements)

References 9 publications

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“…nerve region leads to shortened internode as well as reduced nerve conduction. BACE1 is also required for initial and optimal remyelination of corpus callosum axons, as demonstrated in cuprizone-induced demyelination experiments (Treiber et al, 2012). …”

Section: Biological Functions Attributable To Bace1-cleavable Substratesmentioning

confidence: 98%

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Yan

2017

Front. Mol. Neurosci.

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BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years. We and others have shown that BACE1 is not only a critical enzyme for testing the “Amyloid Hypothesis” associated with Alzheimer’s pathogenesis, but also important for various functions such as axon growth and pathfinding, astrogenesis, neurogenesis, hyperexcitation, and synaptic plasticity. BACE2 appears to play different roles such as glucose homeostasis and pigmentation. This knowledge regarding BACE1 functions is critical for monitoring the safe use of BACE1 inhibitors in humans.

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Section: Biological Functions Attributable To Bace1-cleavable Substratesmentioning

confidence: 98%

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Yan

2017

Front. Mol. Neurosci.

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“…Merck researchers have developed several lead compounds that were identified through screening of a million compounds from drug libraries, and these have produced a large number of molecules that potently inhibit BACE1 in vitro. [107][108][109][110][111] Trials of selected drugs in primate models have shown very promising potential, with near-complete inhibition of Aβ levels in the brain and CSF. 112,113 Compound MK-8931 has now progressed to Phase II clinical trials, and presentations at conferences suggest this is currently the most advanced BACE1 inhibitor in human trials.…”

Section: Bace1 Inhibitors In Preclinical and Clinical Trialsmentioning

confidence: 99%

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

Evin

Barakat

2014

DNND

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Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.

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“…This has since been attributed to perturbations in neuregulin (NRG) signaling. A further study demonstrated that while the effect of BACE1 knockout on myelination is much more subtle in adult mice, this might be sufficient to cause disturbances in higher brain functions [45]. Both NRG1 and NRG3 are substrates for BACE1, and their proteolytic degradation is inhibitory to myelination [39][40][41].…”

Section: Targeting Bace1 Therapeutically -Is It a Good Idea?mentioning

confidence: 99%

Modulation of BACE1 Activity as a Potential Therapeutic Strategy for Treating Alzheimer’s Disease

Klaver

Tesco

2014

Drug Design and Discovery in Alzheimer's Disease

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BACE1 in central nervous system myelination revisited

Cited by 17 publications

References 9 publications

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

Modulation of BACE1 Activity as a Potential Therapeutic Strategy for Treating Alzheimer’s Disease

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BACE1 in central nervous system myelination revisited

Cited by 17 publications

References 9 publications

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Critical analysis of the use of &beta;-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer&#39;s disease

Modulation of BACE1 Activity as a Potential Therapeutic Strategy for Treating Alzheimer’s Disease

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Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease