Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein

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Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein. / Wang, Chao; Sun, Binggui; Zhou, Yungui; Grubb, Anders; Gan, Li.

In: Journal of Biological Chemistry, Vol. 287, No. 47, 2012, p. 39834-39841.

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Wang, Chao ; Sun, Binggui ; Zhou, Yungui ; Grubb, Anders ; Gan, Li. / Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 47. pp. 39834-39841.

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TY - JOUR

T1 - Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein

AU - Wang, Chao

AU - Sun, Binggui

AU - Zhou, Yungui

AU - Grubb, Anders

AU - Gan, Li

PY - 2012

Y1 - 2012

N2 - Accumulation of amyloid-beta (A beta), believed to be a key trigger of Alzheimer disease (AD), could result from impaired clearance mechanisms. Previously, we showed that the cysteine protease cathepsin B (CatB) degrades A beta, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the A beta-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers A beta levels by enhancing CatB-mediated A beta degradation in hAPP(FAD) mice. However, because a vast majority of AD patients do not carry familial mutations, we investigated how the CysC-CatB axis affects A beta levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total A beta and A beta 42 levels in hAPP(WT) mice, whereas CatB deletion increased A beta levels. To determine whether neuron-derived CatB degrades A beta in vivo, we generated transgenic mice overexpressing CatB under the control of a neuron-specific enolase promoter. Enhancing neuronal CatB activity in hAPP(WT) mice significantly lowered A beta 42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of A beta 42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower A beta, especially A beta 42, in AD patients with or without familial mutations.

AB - Accumulation of amyloid-beta (A beta), believed to be a key trigger of Alzheimer disease (AD), could result from impaired clearance mechanisms. Previously, we showed that the cysteine protease cathepsin B (CatB) degrades A beta, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the A beta-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers A beta levels by enhancing CatB-mediated A beta degradation in hAPP(FAD) mice. However, because a vast majority of AD patients do not carry familial mutations, we investigated how the CysC-CatB axis affects A beta levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total A beta and A beta 42 levels in hAPP(WT) mice, whereas CatB deletion increased A beta levels. To determine whether neuron-derived CatB degrades A beta in vivo, we generated transgenic mice overexpressing CatB under the control of a neuron-specific enolase promoter. Enhancing neuronal CatB activity in hAPP(WT) mice significantly lowered A beta 42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of A beta 42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower A beta, especially A beta 42, in AD patients with or without familial mutations.

U2 - 10.1074/jbc.M112.371641

DO - 10.1074/jbc.M112.371641

M3 - Article

C2 - 23024364

VL - 287

SP - 39834

EP - 39841

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 47

ER -