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O3‐04‐06: Significantly altered BACE1 levels have been found in the blood of Alzheimer's disease and MCI subjects
Author(s) -
Shen Yong,
Sabbagh Marwan,
Nural Hikmet,
He Ping,
Cheng Xin,
Ewers Michael,
Hampel Harald
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.453
Subject(s) - biomarker , apolipoprotein e , pathological , disease , cognitive impairment , alzheimer's disease , medicine , memory impairment , oncology , endocrinology , cognition , biology , biochemistry , psychiatry
Background: The progressive formation of amyloid plaques consisting of the 4-KD amyloid b-peptide (Ab) has long been considered the pathological hallmark of Alzheimer’s disease (AD). Beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) to produce Ab. We and others recently discovered that BACE1 activity was significantly increased in sporadic AD brains (Yang et al., 2003) and that the concentrations of both CSF BACE1 enzymatic activity and protein were significantly increased in subjects with amnestic mild cognitive impairment (MCI) (Zhong et al., 2007). Methods: We have hypothesized that by using BACE1 as a biomarker candidate in plasma, it may aid in early detection and prediction of AD in the at risk predementia MCI stage. Post-mortem studies have shown that the APOE-e4 genotype is associated with an increase in Ab production, and the e4 isoform may regulate the generation of Ab. Moreover, memory declined in APOE-e4 carriers even before the symptomatic presentation of MCI and before the age of 60. Results: Interestingly, we have found that the highest significantly elevated BACE1 concentrations were in the CSF of MCI APOEe4 carriers (Ewers et al., 2008). Lumbar punctures, however, are considered an invasive procedure it may be difficult to obtain the sample size necessary for biomarker validation studies, or for a broad clinical screening with a diagnostic indicator. Therefore, potential biomarkers from a more accessible source, such as blood plasma from certain types of cells, are critical for advancement. To our knowledge, this is the first time blood has been examined for BACE1 functional proteins and enzyme activity, as well as the enzymatic product, sAPPb and total Ab1-x. As expected, we found significant changes among BACE1 functional proteins in the blood from subjects with MCI and AD compared to age-matched cognitively normal controls. Conclusions: These finding are highly relevant for the improved hypothesis driven generation of biomarkers for AD, regarding early detection and prediction, as well as for assessment of mechanisms for amyloid lowering compounds currently in phase I-III clinical trials. Potential molecular mechanisms of BACE 1 in the blood will be discussed in this paper.