Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice

Shaowu Cheng; Willayat Y. Wani; David A. Hottman; Angela Jeong; Dongfeng Cao; Kyle J. LeBlanc; Paul Saftig; Jianhua Zhang; Ling Li

doi:10.1111/jnc.14048

Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice

Shaowu Cheng, Willayat Y. Wani, David A. Hottman, Angela Jeong, Dongfeng Cao, Kyle J. LeBlanc, Paul Saftig, Jianhua Zhang, Ling Li

Experimental and Clinical Pharmacology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral β-amyloidosis in amyloid-β precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/− compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aβ were found in the brain. There were also no differences in APP processing, the levels of two other Aβ-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/− mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral β-amyloidosis and autophagy in APP/PS1 transgenic mice. (Figure presented.).

Original language	English (US)
Pages (from-to)	297-304
Number of pages	8
Journal	Journal of Neurochemistry
Volume	142
Issue number	2
DOIs	https://doi.org/10.1111/jnc.14048
State	Published - Jul 1 2017

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health grants NS064090 (JZ), AG031846 (LL), NIH/NIA T32 AG029796 9 (for DAH), the Center on Aging Fesler-Lampert Chair in Aging Studies grant, the College of Pharmacy GAP grant, the Academic Health Center Faculty Research Development Program of the University of Minnesota (LL), U.S. Department of Health and Human Services, and National Institute of Neurological Disorders and Stroke (NS064090). We would like to thank Hailin Lu and Andrea Gram for genotyping and maintaining the mouse colonies. No conflict of interest. All experiments were conducted in compliance with the ARRIVE guidelines.

Publisher Copyright:
© 2017 International Society for Neurochemistry

Keywords

Alzheimer's disease
Amyloid-β
Cathepsin D
LAMP2
LC3
p62

Publisher link

10.1111/jnc.14048

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499660

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@article{ba677f0243be47ef9f793e5874e98f0f,

title = "Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice",

abstract = "Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral β-amyloidosis in amyloid-β precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/− compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aβ were found in the brain. There were also no differences in APP processing, the levels of two other Aβ-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/− mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral β-amyloidosis and autophagy in APP/PS1 transgenic mice. (Figure presented.).",

keywords = "Alzheimer's disease, Amyloid-β, Cathepsin D, LAMP2, LC3, p62",

author = "Shaowu Cheng and Wani, {Willayat Y.} and Hottman, {David A.} and Angela Jeong and Dongfeng Cao and LeBlanc, {Kyle J.} and Paul Saftig and Jianhua Zhang and Ling Li",

note = "Funding Information: This work was supported in part by the National Institutes of Health grants NS064090 (JZ), AG031846 (LL), NIH/NIA T32 AG029796 9 (for DAH), the Center on Aging Fesler-Lampert Chair in Aging Studies grant, the College of Pharmacy GAP grant, the Academic Health Center Faculty Research Development Program of the University of Minnesota (LL), U.S. Department of Health and Human Services, and National Institute of Neurological Disorders and Stroke (NS064090). We would like to thank Hailin Lu and Andrea Gram for genotyping and maintaining the mouse colonies. No conflict of interest. All experiments were conducted in compliance with the ARRIVE guidelines. Publisher Copyright: {\textcopyright} 2017 International Society for Neurochemistry",

year = "2017",

month = jul,

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doi = "10.1111/jnc.14048",

language = "English (US)",

volume = "142",

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T1 - Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice

AU - Cheng, Shaowu

AU - Wani, Willayat Y.

AU - Hottman, David A.

AU - Jeong, Angela

AU - Cao, Dongfeng

AU - LeBlanc, Kyle J.

AU - Saftig, Paul

AU - Zhang, Jianhua

AU - Li, Ling

N1 - Funding Information: This work was supported in part by the National Institutes of Health grants NS064090 (JZ), AG031846 (LL), NIH/NIA T32 AG029796 9 (for DAH), the Center on Aging Fesler-Lampert Chair in Aging Studies grant, the College of Pharmacy GAP grant, the Academic Health Center Faculty Research Development Program of the University of Minnesota (LL), U.S. Department of Health and Human Services, and National Institute of Neurological Disorders and Stroke (NS064090). We would like to thank Hailin Lu and Andrea Gram for genotyping and maintaining the mouse colonies. No conflict of interest. All experiments were conducted in compliance with the ARRIVE guidelines. Publisher Copyright: © 2017 International Society for Neurochemistry

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral β-amyloidosis in amyloid-β precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/− compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aβ were found in the brain. There were also no differences in APP processing, the levels of two other Aβ-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/− mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral β-amyloidosis and autophagy in APP/PS1 transgenic mice. (Figure presented.).

AB - Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral β-amyloidosis in amyloid-β precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/− compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aβ were found in the brain. There were also no differences in APP processing, the levels of two other Aβ-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/− mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral β-amyloidosis and autophagy in APP/PS1 transgenic mice. (Figure presented.).

KW - Alzheimer's disease

KW - Amyloid-β

KW - Cathepsin D

KW - LAMP2

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KW - p62

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Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice

Abstract

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Keywords

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