Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease

Hong Jiang, Harald Hampel, David Prvulovic, Anders Wallin, Kaj Blennow, Rena Li, Yong Shen, Hong Jiang, Harald Hampel, David Prvulovic, Anders Wallin, Kaj Blennow, Rena Li, Yong Shen

Abstract

We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.

Figures

Figure 1
Figure 1
The baseline levels of soluble TNF receptors, type I and type 2 (sTNFR1 and sTNFR2) in CSF correlate positively to the TACE activity in AD patients.
Figure 2
Figure 2
The baseline levels of soluble TNF receptors type 1 and type 2 (sTNFR1 and sTNFR2) in CSF correlate positively to the TACE activity in aged-matched healthy individuals.
Figure 3
Figure 3
The baseline levels of soluble TNF receptors, type 1 and type 2 (sTNFR1 and sTNFR2) in CSF correlate positively to the TACE activity in MCI patients.
Figure 4
Figure 4
The levels of soluble TNF receptor type 1 (sTNFR1) in CSF correlate positively to the soluble TNF receptor type 2 (sTNFR2) in the CSF between AD patients and aged-matched healthy controls.
Figure 5
Figure 5
The levels of soluble TNF receptor type 1 (sTNFR1) in CSF correlate positively to the soluble TNF receptor type 2 (sTNFR2) in the CSF among the MCI patients.

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