Bace1 Levels Are Increased in Plasma Of Alzheimer’S Disease Patients Compared with Matched Cognitively Healthy Controls

Manzine, Patrícia Regina; Souza, Matheus da Silva; Cominetti, Márcia Regina

doi:10.2217/pme-2016-0033

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…This biochemical characterization may serve for a better evaluation of BACE1/β-secretase activity as a potential biomarker for AD. BACE1 has been considered as a promising candidate biomarker due to its role in the generation of Aβ and the demonstration that the β-secretase activity can be assayed in CSF and plasma (Gonzales et al, 2011;Holsinger et al, 2004;Manzine et al, 2016;Shen et al, 2018;Wu et al, 2008;Wu et al, 2012;Zetterberg et al, 2008). However, to date, little is known about the cell biology and biochemistry of BACE1 in CSF.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cerebrospinal Fluid BACE1 Species

et al. 2019

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Background: The primary neuronal β-secretase in the brain is the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 is the main protease responsible for the amyloidogenic processing of the amyloid precursor protein (APP) leading to Aβ generation. Previous studies have suggested the potential of cerebrospinal fluid (CSF) β-secretase activity to be a diagnostic biomarker for Alzheimer's disease (AD), but these studies have not demonstrated consistent changes in AD CSF. Therefore, further biochemical characterization of BACE1 protein and β-secretase activity in AD CSF is needed. Methods: β-Secretase activity was determined in CSF from AD patients (n= 19) and age-matched non-AD controls (n= 19) using a fluorogenic substrate in the absence and presence of a BACE1 inhibitor. BACE1 protein was characterized by lectin-binding, immunoprecipitation, blue native-PAGE and western blotting using specific antibodies. Results: We show that the majority of the β-secretase activity in the CSF is not inhibited by a specific BACE1 inhibitor, and that β-secretase activity attributable to BACE1 is higher in AD subjects. BACE1 is present in human CSF, both as immature forms of ~50 kDa that retain the prodomain and mature forms of ~70 kDa that probably comprise truncated and full-length species. CSF-BACE1 forms large hetero-complexes containing distinct species. Immunoblotting with an antibody against the C-terminus of BACE1 revealed significantly higher levels of the 70-kDa full-length BACE1, while the 50 kDa immature form remained unaltered. When the 70-kDa band was probed with an antibody against the N-terminus of BACE1, which does not discriminate between truncated and full-length forms, no increase was observed, suggesting that truncated forms of BACE1 do not increase in AD. Lopez-Font et al. 3 Conclusions: The activity of β-secretase in the CSF cannot be attributed only to BACE1. Both mature and immature species of BACE1 occur as heteromers. Only mature full-length BACE1 shows increased levels in AD CSF. The complexity of BACE1 species in CSF has to be taken into consideration for the determination of BACE1 activity and protein levels in CSF as biomarkers of AD.

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Section: Discussionmentioning

confidence: 99%

Characterization of Cerebrospinal Fluid BACE1 Species

et al. 2019

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“…The lncRNA BACE1 level was dramatically up-regulated in AD patient’s plasma compared with normal control subjects, while no significantly alteration of plasma lncRNA 17A, 51A and BC200. Accordantly, Manzine et al also confirmed that plasma BACE1 level was elevated in AD patients [86]. However, Marison et al proved that there was no dramatically difference of BACE1 expression in blood between control, AD and non-AD neuropathology’s individuals.…”

Section: Circulating Lncrnas and Alzheimer’s Diseasementioning

confidence: 92%

The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease

Zhao¹,

Zhang²,

Zhang³

et al. 2019

Aging and disease

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Alzheimer’s disease (AD) is a neurodegenerative disorder and one of the leading causes of disability and mortality in the late life with no curative treatment currently. Thus, it is urgently to establish sensitive and non-invasive biomarkers for AD diagnosis, particularly in the early stage. Recently, emerging number of microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are considered as effective biomarkers in various diseases as they possess characteristics of stable, resistant to RNAase digestion and many extreme conditions in circulatory fluid. This review highlights recent advances in the identification of the aberrantly expressed miRNAs and lncRNAs in circulatory network for detection of AD. We summarized the abnormal expressed miRNAs in blood and cerebrospinal fluid (CSF), and detailed discussed the functions and molecular mechanism of serum or plasma miRNAs-miR-195, miR-155, miR-34a, miR-9, miR-206, miR-125b and miR-29 in the regulation of AD progression. In addition, we also elaborated the role of circulating lncRNA major including beta-site APP cleaving enzyme 1 (BACE1) and its antisense lncRNA BACE1-AS in AD pathological advancement. In brief, confirming the aberrantly expressed circulating miRNAs and lncRNAs will provide an effective testing tools for treatment of AD in the future.

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“…Some studies employed assays based on polyclonal antibodies [34,68], which do not support the reproducibility of the assays on the longer term (cfr. long-term supply of antibodies with steady characteristics, lot-tolot consistency of the assay, etc.).…”

Section: Methodological and Technological Challengesmentioning

confidence: 99%

“…Both BACE1 activity and protein concentrations in blood (mostly plasma but in some cases serum) are significantly increased in MCI individuals or patients with ADD compared to HC individuals, with a trend across different disease stages reflecting the direction of expression of the reported CSF biomarkers [34][35][36].…”

Section: Bace1 Biomarkers In Plasmamentioning

confidence: 99%

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

Vanmechelen¹,

Zetterberg

Galgani

et al. 2020

Alz Res Therapy

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β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

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Bace1 Levels Are Increased in Plasma Of Alzheimer’S Disease Patients Compared with Matched Cognitively Healthy Controls

Abstract: Blood-based diagnostic tools are desired to improve AD diagnosis. BACE1 plasma levels could provide an additional diagnostic tool for AD in association with neuropsychological tests.

Cited by 7 publications

References 43 publications

Characterization of Cerebrospinal Fluid BACE1 Species

Characterization of Cerebrospinal Fluid BACE1 Species

The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

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