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. 2014 Jan;184(1):141-7.
doi: 10.1016/j.ajpath.2013.10.002.

High activities of BACE1 in brains with mild cognitive impairment

Xin Cheng  1 , Ping He  2 , Taehee Lee  3 , Hailan Yao  4 , Rena Li  5 , Yong Shen  6
Affiliations

High activities of BACE1 in brains with mild cognitive impairment

Xin Cheng et al. Am J Pathol. 2014 Jan.

Abstract

We recently discovered elevated β-secretase 1 (BACE1) activity in brains with sporadic Alzheimer disease (AD). Moreover, we also found high levels of BACE1 enzymatic activity in the cerebrospinal fluid from patients with both mild cognitive impairment (MCI) and AD. These results suggest that elevation of BACE1 enzymatic activity may occur early or may contribute to AD. We therefore examined whether BACE1 enzymatic activity was changed in MCI brains. BACE1 activity and tumor necrosis factor (TNF)-α levels were measured by enzymatic assay and ELISA in the temporal cortex from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 healthy controls. We found a significant increase in BACE1 activity and protein level in brains of MCI and AD patients. Moreover, increased BACE1 activity correlated with plaque numbers and cognition status. We also found an increase in TNF-α in MCI brains. In vitro study revealed that TNF-α rather than other cytokines can up-regulate BACE1 protein expression. These findings suggest that BACE1 increase occurs early in MCI and is possibly induced by TNF-α and that BACE1 enzymatic activity may be important for conversion of MCI to AD.

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Figures

Figure 1
Figure 1
A: Western blot shows BACE1 protein expression in the temporal cortex from the brains of non-demented (ND) controls, Alzheimer disease (AD) patients, and mild cognitive impairment (MCI) patients. Quantitative analysis reveals a significant increase in BACE1 protein levels in the brains of AD and MCI patients compared with ND controls. B: BACE1 ELISA confirms the results of Western blot. C: BACE1 activity assay reveals elevated BACE1 activity in brains of AD and MCI patients compared with ND controls. The activity was normalized to the input protein amount and indicated as an arbitrary unit. n = 18 for each group. ∗P < 0.05 versus ND brains.
Figure 2
Figure 2
A: BACE1 enzymatic activity significantly correlates with plaque numbers in mild cognitive impairment (MCI) brains by linear regression analysis (rs = 0.48, P < 0.05). B: Among the 11 MCI patients who had their last MMSE before death, BACE1 enzymatic activity negatively correlates with their cognitive function (MMSE scores) by linear regression analysis (rs = −0.67, P < 0.05).
Figure 3
Figure 3
A: TNF-α concentration elevates in mild cognitive impairment (MCI) or Alzheimer disease (AD) brains compared with non-demented (ND) brains. n = 18 each group. ∗P < 0.05 versus ND brains. B: With exogenous TNF-α treatment on human neurons, BACE1 protein expression levels elevate in a dose-dependent manner, whereas IL-1β appears to have little effect on BACE1 expression. C: HEK293 cells transfected with a BACE1 promoter luciferase reporter vector were treated with different concentrations of TNF-α with or without NF-κB inhibitor. TNF-α induces BACE1 promoter activity in a dose-dependent manner, whereas NF-κB inhibits TNF-α–induced BACE1 promoter activity.
Figure 4
Figure 4
HEK293 cells transfected with a BACE1 promoter luciferase reporter vector were treated with different concentrations of IL-8 (A), IL-12 (B), and GM-CSF (C). There are few effects of IL-8, IL-12, and GM-CSF treatments on BACE1 promoter activity.
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