Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Abstract

Context: Elevated ␤-secretase (␤-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported.Objective: To examine whether BACE1 can be identified in the CSF of patients with MCI.Design: We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-␤ peptide levels using a sandwich enzyme-linked immunosorbent assay.Setting: Two independent research centers.Participants: Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls.Main Outcome Measures: BACE1 levels and enzymatic activities and amyloid-␤ peptide levels. Conclusion: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD. Psychiatry. 2007;64:718-726 A LZHEIMER DISEASE (AD) IS characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the 4-kDa amyloid-␤ peptide (A␤) in the brain. Arch Gen1 ␤-Secretase (␤-site amyloid precursor protein-cleaving en-2 is one of the 2 key enzymes in amyloid precursor protein (APP) processing. Amyloid-␤ peptide results from cleavage of APP initially by BACE1 to produce a C99 fragment and release soluble APP␤; C99 is then further cleaved by ␥-secretase, leading to A␤. Increased BACE1 activity and elevated levels of insoluble A␤ have been shown in the brains of patients with sporadic AD. 3,4 Because cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain could potentially be reflected in CSF. The CSF-based detection of BACE1 levels and activity might be valuable in aiding the early diagnosis of AD, especially in patients with mild cognitive impairment (MCI), who show a higher risk of AD.5 Several recent studies [6][7][8] showed that BACE1 activity can be detected in the CSF. However, whether changes could occur in BACE1 activity or protein levels in the CSF of patients with AD or MCI remains unknown.In the present study, we quantitatively analyzed the enzymatic activities and protein levels of BACE1 and total A␤ levels in CSF samples from 208 individuals. We aim to determine whether BACE1 levels and activity can be detected in CSF, whether they are altered in AD compared with healthy aging, and whether levels of BACE1 protein and activity may be useful to discriminate patients with AD or MCI from healthy individuals.

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

“…The contrast between BACE1's essential role in cognitive, emotional and synaptic functions 19,20 and its pathophysiological dysregulation in Alzheimer's disease 38,39 highlights the regulatory complexity of this protein. Owing to the consequences of its dysregulation, BACE1 gene expression must normally maintain tight robust regulatory control.…”

Biomarkers for Alzheimer’s disease and other forms of dementia: Clinical needs, limitations and future aspects

“…The CSF biomarkers total tau (tTau), hyperphosphorylated tau (pTau), and the 42 amino acid form of Aβ (Aβ-42) are now established markers for AD (Zetterberg et al, 2003) and can identify AD in the early, MCI stage of the disease with high accuracy (Hansson et al, 2006). CSF of AD and MCI patients shows decreased values of Aβ-42 and increased total tau (tTau) or phosphorylated tau (pTau) (Ewers et al, 2007). Recent studies have been focused in investigating if the pattern of different length Aβ peptides could enhance the diagnostic power.…”

New Frontiers in Alzheimer's Disease Diagnosis

“…Several independent observations indicate the presence of higher BACE1 levels and activity in the CSF of MCI and AD samples when compared to controls [97][98][99][100]. BACE1 activity is also increased in CJD samples [101] suggesting common pathological mechanisms among both diseases.…”