Diverse protein profiles in CNS myeloid cells and CNS tissue from lipopolysaccharide- and vehicle-injected APPSWE/PS1ΔE9 transgenic mice implicate cathepsin Z in alzheimer’s disease

Camilla Thygesen, Laura Ilkjær, Stefan J. Kempf, Anne Louise Hemdrup, Christian Ulrich von Linstow, Alicia A. Babcock, Sultan Darvesh, Martin R. Larsen, Bente Finsen*

*Corresponding author for this work

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Abstract

Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

Original languageEnglish
Article number397
JournalFrontiers in cellular neuroscience
Volume12
Number of pages21
ISSN1662-5102
DOIs
Publication statusPublished - Nov 2018

Fingerprint

Cathepsin Z
Myeloid Cells
Alzheimer Disease
Microglia
Proteins
Neocortex
Proteome
Pathology
Clusterin
Amyloid Plaques
Intraperitoneal Injections
Peptide Hydrolases

Keywords

  • Alzheimer’s disease
  • Amyloid precursor protein
  • Apolipoprotein E
  • Cathepsin Z
  • Microglia
  • Perivascular cells
  • Quantitative proteomics
  • Systemic inflammation

Cite this

@article{f8f13b5256a64f578f62b1d18ed6499f,
title = "Diverse protein profiles in CNS myeloid cells and CNS tissue from lipopolysaccharide- and vehicle-injected APPSWE/PS1ΔE9 transgenic mice implicate cathepsin Z in alzheimer’s disease",
abstract = "Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.",
keywords = "Alzheimer’s disease, Amyloid precursor protein, Apolipoprotein E, Cathepsin Z, Microglia, Perivascular cells, Quantitative proteomics, Systemic inflammation",
author = "Camilla Thygesen and Laura Ilkj{\ae}r and Kempf, {Stefan J.} and Hemdrup, {Anne Louise} and {von Linstow}, {Christian Ulrich} and Babcock, {Alicia A.} and Sultan Darvesh and Larsen, {Martin R.} and Bente Finsen",
year = "2018",
month = "11",
doi = "10.3389/fncel.2018.00397",
language = "English",
volume = "12",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",
publisher = "Frontiers Media S.A.",

}

Diverse protein profiles in CNS myeloid cells and CNS tissue from lipopolysaccharide- and vehicle-injected APPSWE/PS1ΔE9 transgenic mice implicate cathepsin Z in alzheimer’s disease. / Thygesen, Camilla; Ilkjær, Laura; Kempf, Stefan J.; Hemdrup, Anne Louise; von Linstow, Christian Ulrich; Babcock, Alicia A.; Darvesh, Sultan; Larsen, Martin R.; Finsen, Bente.

In: Frontiers in cellular neuroscience, Vol. 12, 397, 11.2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Diverse protein profiles in CNS myeloid cells and CNS tissue from lipopolysaccharide- and vehicle-injected APPSWE/PS1ΔE9 transgenic mice implicate cathepsin Z in alzheimer’s disease

AU - Thygesen, Camilla

AU - Ilkjær, Laura

AU - Kempf, Stefan J.

AU - Hemdrup, Anne Louise

AU - von Linstow, Christian Ulrich

AU - Babcock, Alicia A.

AU - Darvesh, Sultan

AU - Larsen, Martin R.

AU - Finsen, Bente

PY - 2018/11

Y1 - 2018/11

N2 - Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

AB - Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

KW - Alzheimer’s disease

KW - Amyloid precursor protein

KW - Apolipoprotein E

KW - Cathepsin Z

KW - Microglia

KW - Perivascular cells

KW - Quantitative proteomics

KW - Systemic inflammation

U2 - 10.3389/fncel.2018.00397

DO - 10.3389/fncel.2018.00397

M3 - Journal article

VL - 12

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

M1 - 397

ER -