β-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau.

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid β production, which is a pathological hallmark of Alzheimer's disease (AD). The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. In the AD group, positive correlations between BACE1 activity and soluble APP β, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid β1-42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.

Tsolakidou A ，Alexopoulos P ，Guo LH ，Grimmer T ，Westerteicher C ，Kratzer M ，Jiang M ，Bujo H ，Roselli F ，Leante MR ，Livrea P ，Kurz A ，Perneczky R ... -  《-》

BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology.

Mulder SD ，van der Flier WM ，Verheijen JH ，Mulder C ，Scheltens P ，Blankenstein MA ，Hack CE ，Veerhuis R ... -  《-》

Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease.

Zetterberg H ，Andreasson U ，Hansson O ，Wu G ，Sankaranarayanan S ，Andersson ME ，Buchhave P ，Londos E ，Umek RM ，Minthon L ，Simon AJ ，Blennow K ... -  《-》

Interrelations between CSF soluble AβPPβ, amyloid-β 1-42, SORL1, and tau levels in Alzheimer's disease.

Alexopoulos P ，Guo LH ，Tsolakidou A ，Kratzer M ，Grimmer T ，Westerteicher C ，Jiang M ，Bujo H ，Diehl-Schmid J ，Kurz A ，Perneczky R ... -  《-》

Decrease in brain soluble amyloid precursor protein β (sAPPβ) in Alzheimer's disease cortex.

Amyloid-β peptide (Aβ) is generated by sequential cleavage of the amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, or BACE1) and γ-secretase. Several reports demonstrate increased BACE1 enzymatic activity in brain and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) subjects, suggesting that an increase in BACE1-mediated cleavage of APP drives amyloid pathophysiology in AD. BACE1 cleavage of APP leads to the generation of a secreted N-terminal fragment of APP (sAPPβ). To relate BACE1 activity better to endogenous APP processing in AD and control brains, we have directly measured brain sAPPβ levels using a novel APP β-site specific enzyme-linked immunosorbent assay. We demonstrate a significant reduction in brain cortical sAPPβ levels in AD compared with control subjects. In the same brain samples, BACE1 activity was unchanged, full-length APP and sAPPα levels were significantly reduced, and Aβ peptides were significantly elevated. In conclusion, a reduction in cortical brain sAPPβ together with unchanged BACE1 activity suggests that this is due to reduced full-length APP substrate in late-stage AD subjects. These results highlight the need for multiparameter analysis of the amyloidogenic process to understand better AD pathophysiology in early vs. late-stage AD.

Wu G ，Sankaranarayanan S ，Hsieh SH ，Simon AJ ，Savage MJ ... -  《-》