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Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) as a biological candidate marker of Alzheimer's disease.
Scand J Clin Lab Invest. 2009; 69(1):8-12.SJ

Abstract

Alzheimer's disease (AD) is characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid beta-peptide (Abeta) in the brain. Pathological mechanisms are already active early in the presymptomatic stage of AD. BACE1, beta-secretase, is one of the two key enzymes in amyloid precursor protein (APP) processing; the other being gamma-secretase. The Abeta peptide results from cleavage of APP initially by BACE1 to produce the C99 fragment and releases soluble APPbeta (sAPPbeta); C99 is then further cleaved by gamma-secretase leading to the Abeta peptide. Increased BACE1 activity and elevated levels of insoluble Abeta peptide have been shown in brain tissue of patients with sporadic AD. Since the CSF is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain can potentially be reflected in CSF. Therefore, CSF-based detection of BACE1 levels and activity might be valuable in aiding early detection and prediction, particularly in preclinical or even presymptomatic subjects who are at risk of AD. Recently, we were among the first groups to quantitatively analyse the enzymatic activities and protein levels of BACE1 in the CSF. Preliminary research using recently developed BACE1 ELISAs, BACE1 enzymatic activity, sAPPbeta and total Abeta1-x ELISAs were used by examining these hypothesis driven functional candidate markers in subjects with clinically diagnosed AD and amnestic MCI. Two sandwich ELISAs were used and BACE1 enzymatic activities were seen by synthetic fluorescence substrate and total Abeta levels by sandwich-ELISA. Moreover, elevated CSF levels of BACE1 protein were associated with an increased risk ratio in MCI. Interestingly, amnestic MCI subjects showed increased levels of BACE1 activity compared to HC and AD patients. For total Abeta and tau, increased CSF levels were associated with a higher risk of MCI compared to HC as well. BACE1 activity was significantly correlated with BACE1 protein concentration and total Abeta levels, with Abeta being itself correlated with the BACE1 protein level. Currently, independent studies are ongoing to validate BACE1 and functionally associated proteins as candidate biomarkers for early detection, prediction, progression as well as for biological activity in AD.

Authors+Show Affiliations

1Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. harald.hampel@tcd.ieNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18609117

Citation

Hampel, Harald, and Yong Shen. "Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) as a Biological Candidate Marker of Alzheimer's Disease." Scandinavian Journal of Clinical and Laboratory Investigation, vol. 69, no. 1, 2009, pp. 8-12.
Hampel H, Shen Y. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) as a biological candidate marker of Alzheimer's disease. Scand J Clin Lab Invest. 2009;69(1):8-12.
Hampel, H., & Shen, Y. (2009). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) as a biological candidate marker of Alzheimer's disease. Scandinavian Journal of Clinical and Laboratory Investigation, 69(1), 8-12. https://doi.org/10.1080/00365510701864610
Hampel H, Shen Y. Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) as a Biological Candidate Marker of Alzheimer's Disease. Scand J Clin Lab Invest. 2009;69(1):8-12. PubMed PMID: 18609117.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) as a biological candidate marker of Alzheimer's disease. AU - Hampel,Harald, AU - Shen,Yong, PY - 2008/7/9/pubmed PY - 2009/3/21/medline PY - 2008/7/9/entrez SP - 8 EP - 12 JF - Scandinavian journal of clinical and laboratory investigation JO - Scand J Clin Lab Invest VL - 69 IS - 1 N2 - Alzheimer's disease (AD) is characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid beta-peptide (Abeta) in the brain. Pathological mechanisms are already active early in the presymptomatic stage of AD. BACE1, beta-secretase, is one of the two key enzymes in amyloid precursor protein (APP) processing; the other being gamma-secretase. The Abeta peptide results from cleavage of APP initially by BACE1 to produce the C99 fragment and releases soluble APPbeta (sAPPbeta); C99 is then further cleaved by gamma-secretase leading to the Abeta peptide. Increased BACE1 activity and elevated levels of insoluble Abeta peptide have been shown in brain tissue of patients with sporadic AD. Since the CSF is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain can potentially be reflected in CSF. Therefore, CSF-based detection of BACE1 levels and activity might be valuable in aiding early detection and prediction, particularly in preclinical or even presymptomatic subjects who are at risk of AD. Recently, we were among the first groups to quantitatively analyse the enzymatic activities and protein levels of BACE1 in the CSF. Preliminary research using recently developed BACE1 ELISAs, BACE1 enzymatic activity, sAPPbeta and total Abeta1-x ELISAs were used by examining these hypothesis driven functional candidate markers in subjects with clinically diagnosed AD and amnestic MCI. Two sandwich ELISAs were used and BACE1 enzymatic activities were seen by synthetic fluorescence substrate and total Abeta levels by sandwich-ELISA. Moreover, elevated CSF levels of BACE1 protein were associated with an increased risk ratio in MCI. Interestingly, amnestic MCI subjects showed increased levels of BACE1 activity compared to HC and AD patients. For total Abeta and tau, increased CSF levels were associated with a higher risk of MCI compared to HC as well. BACE1 activity was significantly correlated with BACE1 protein concentration and total Abeta levels, with Abeta being itself correlated with the BACE1 protein level. Currently, independent studies are ongoing to validate BACE1 and functionally associated proteins as candidate biomarkers for early detection, prediction, progression as well as for biological activity in AD. SN - 1502-7686 UR - https://www.unboundmedicine.com/medline/citation/18609117/Beta_site_amyloid_precursor_protein_cleaving_enzyme_1__BACE1__as_a_biological_candidate_marker_of_Alzheimer's_disease_ L2 - https://www.tandfonline.com/doi/full/10.1080/00365510701864610 DB - PRIME DP - Unbound Medicine ER -