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Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis... Full description

Journal Title: Nature medicine 2014-10, Vol.20 (10), p.1157-1164
Main Author: Minami, S Sakura
Other Authors: Min, Sang-Won , Krabbe, Grietje , Wang, Chao , Zhou, Yungui , Asgarov, Rustam , Li, Yaqiao , Martens, Lauren H , Elia, Lisa P , Ward, Michael E , Mucke, Lennart , Farese, Jr, Robert V , Gan, Li
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: eScholarship, University of California
ID: ISSN: 1078-8956
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title: Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
format: Article
creator:
  • Minami, S Sakura
  • Min, Sang-Won
  • Krabbe, Grietje
  • Wang, Chao
  • Zhou, Yungui
  • Asgarov, Rustam
  • Li, Yaqiao
  • Martens, Lauren H
  • Elia, Lisa P
  • Ward, Michael E
  • Mucke, Lennart
  • Farese, Jr, Robert V
  • Gan, Li
subjects:
  • 1 Biological
  • Acquired Cognitive Impairment
  • Aging
  • Alzheimer Disease
  • Alzheimer Disease - genetics
  • Alzheimer Disease - metabolism
  • Alzheimer Disease - therapy
  • Alzheimer's Disease
  • Alzheimer's Disease including Alzheimer's Disease Related Dementias
  • Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD
  • Amyloid
  • Amyloid beta
  • Amyloid beta-Peptides - genetics
  • Amyloid beta-Peptides - metabolism
  • Animal
  • Animals
  • Article
  • Basic Medicine
  • Behavioral
  • Biological Sciences
  • Biologiska vetenskaper
  • Brain
  • Brain - metabolism
  • Brain - pathology
  • Brain Disorders
  • Cognition
  • Cognition - physiology
  • Dementia
  • Disease Models
  • Disease Models, Animal
  • endogenous factors
  • Female
  • Frontotemporal Lobar Degeneration
  • Frontotemporal Lobar Degeneration - genetics
  • Frontotemporal Lobar Degeneration - metabolism
  • Frontotemporal Lobar Degeneration - therapy
  • Gene Expression Regulation
  • Granulins
  • Health Sciences
  • Humans
  • Immunity
  • Immunity, Innate - physiology
  • Immunology
  • Inbred C57BL
  • Innate
  • Intercellular Signaling Peptides
  • Intercellular Signaling Peptides and Proteins - deficiency
  • Intercellular Signaling Peptides and Proteins - genetics
  • Intercellular Signaling Peptides and Proteins - metabolism
  • Knockout
  • Male
  • Medical
  • Medical and Health Sciences
  • Medicin och hälsovetenskap
  • Medicinska och farmaceutiska grundvetenskaper
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia
  • Microglia - metabolism
  • Microglia - pathology
  • Natural Sciences
  • Naturvetenskap
  • Neurodegenerative
  • Neurological
  • Neurosciences
  • Neurovetenskaper
  • Peptides
  • Phagocytosis
  • Plaque
  • Plaque, Amyloid - metabolism
  • Plaque, Amyloid - pathology
  • Progranulins
  • Proteins
  • Rats
  • Regulation
  • Social Science
  • Transgenic
  • Up-Regulation
ispartof: Nature medicine, 2014-10, Vol.20 (10), p.1157-1164
description: Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
  • 1546-170X
url: Link


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titleProgranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
creatorMinami, S Sakura ; Min, Sang-Won ; Krabbe, Grietje ; Wang, Chao ; Zhou, Yungui ; Asgarov, Rustam ; Li, Yaqiao ; Martens, Lauren H ; Elia, Lisa P ; Ward, Michael E ; Mucke, Lennart ; Farese, Jr, Robert V ; Gan, Li
creatorcontribMinami, S Sakura ; Min, Sang-Won ; Krabbe, Grietje ; Wang, Chao ; Zhou, Yungui ; Asgarov, Rustam ; Li, Yaqiao ; Martens, Lauren H ; Elia, Lisa P ; Ward, Michael E ; Mucke, Lennart ; Farese, Jr, Robert V ; Gan, Li
descriptionHaploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
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1ISSN: 1546-170X
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3DOI: 10.1038/nm.3672
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languageeng
publisherUnited States: eScholarship, University of California
subject1 Biological ; Acquired Cognitive Impairment ; Aging ; Alzheimer Disease ; Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Alzheimer Disease - therapy ; Alzheimer's Disease ; Alzheimer's Disease including Alzheimer's Disease Related Dementias ; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD ; Amyloid ; Amyloid beta ; Amyloid beta-Peptides - genetics ; Amyloid beta-Peptides - metabolism ; Animal ; Animals ; Article ; Basic Medicine ; Behavioral ; Biological Sciences ; Biologiska vetenskaper ; Brain ; Brain - metabolism ; Brain - pathology ; Brain Disorders ; Cognition ; Cognition - physiology ; Dementia ; Disease Models ; Disease Models, Animal ; endogenous factors ; Female ; Frontotemporal Lobar Degeneration ; Frontotemporal Lobar Degeneration - genetics ; Frontotemporal Lobar Degeneration - metabolism ; Frontotemporal Lobar Degeneration - therapy ; Gene Expression Regulation ; Granulins ; Health Sciences ; Humans ; Immunity ; Immunity, Innate - physiology ; Immunology ; Inbred C57BL ; Innate ; Intercellular Signaling Peptides ; Intercellular Signaling Peptides and Proteins - deficiency ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Knockout ; Male ; Medical ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Medicinska och farmaceutiska grundvetenskaper ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microglia ; Microglia - metabolism ; Microglia - pathology ; Natural Sciences ; Naturvetenskap ; Neurodegenerative ; Neurological ; Neurosciences ; Neurovetenskaper ; Peptides ; Phagocytosis ; Plaque ; Plaque, Amyloid - metabolism ; Plaque, Amyloid - pathology ; Progranulins ; Proteins ; Rats ; Regulation ; Social Science ; Transgenic ; Up-Regulation
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0Minami, S Sakura
1Min, Sang-Won
2Krabbe, Grietje
3Wang, Chao
4Zhou, Yungui
5Asgarov, Rustam
6Li, Yaqiao
7Martens, Lauren H
8Elia, Lisa P
9Ward, Michael E
10Mucke, Lennart
11Farese, Jr, Robert V
12Gan, Li
title
0Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
1Nature medicine
addtitleNat Med
descriptionHaploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
subject
01 Biological
1Acquired Cognitive Impairment
2Aging
3Alzheimer Disease
4Alzheimer Disease - genetics
5Alzheimer Disease - metabolism
6Alzheimer Disease - therapy
7Alzheimer's Disease
8Alzheimer's Disease including Alzheimer's Disease Related Dementias
9Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD
10Amyloid
11Amyloid beta
12Amyloid beta-Peptides - genetics
13Amyloid beta-Peptides - metabolism
14Animal
15Animals
16Article
17Basic Medicine
18Behavioral
19Biological Sciences
20Biologiska vetenskaper
21Brain
22Brain - metabolism
23Brain - pathology
24Brain Disorders
25Cognition
26Cognition - physiology
27Dementia
28Disease Models
29Disease Models, Animal
30endogenous factors
31Female
32Frontotemporal Lobar Degeneration
33Frontotemporal Lobar Degeneration - genetics
34Frontotemporal Lobar Degeneration - metabolism
35Frontotemporal Lobar Degeneration - therapy
36Gene Expression Regulation
37Granulins
38Health Sciences
39Humans
40Immunity
41Immunity, Innate - physiology
42Immunology
43Inbred C57BL
44Innate
45Intercellular Signaling Peptides
46Intercellular Signaling Peptides and Proteins - deficiency
47Intercellular Signaling Peptides and Proteins - genetics
48Intercellular Signaling Peptides and Proteins - metabolism
49Knockout
50Male
51Medical
52Medical and Health Sciences
53Medicin och hälsovetenskap
54Medicinska och farmaceutiska grundvetenskaper
55Mice
56Mice, Inbred C57BL
57Mice, Knockout
58Mice, Transgenic
59Microglia
60Microglia - metabolism
61Microglia - pathology
62Natural Sciences
63Naturvetenskap
64Neurodegenerative
65Neurological
66Neurosciences
67Neurovetenskaper
68Peptides
69Phagocytosis
70Plaque
71Plaque, Amyloid - metabolism
72Plaque, Amyloid - pathology
73Progranulins
74Proteins
75Rats
76Regulation
77Social Science
78Transgenic
79Up-Regulation
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1Min, Sang-Won
2Krabbe, Grietje
3Wang, Chao
4Zhou, Yungui
5Asgarov, Rustam
6Li, Yaqiao
7Martens, Lauren H
8Elia, Lisa P
9Ward, Michael E
10Mucke, Lennart
11Farese, Jr, Robert V
12Gan, Li
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titleProgranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
authorMinami, S Sakura ; Min, Sang-Won ; Krabbe, Grietje ; Wang, Chao ; Zhou, Yungui ; Asgarov, Rustam ; Li, Yaqiao ; Martens, Lauren H ; Elia, Lisa P ; Ward, Michael E ; Mucke, Lennart ; Farese, Jr, Robert V ; Gan, Li
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languageeng
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01 Biological
1Acquired Cognitive Impairment
2Aging
3Alzheimer Disease
4Alzheimer Disease - genetics
5Alzheimer Disease - metabolism
6Alzheimer Disease - therapy
7Alzheimer's Disease
8Alzheimer's Disease including Alzheimer's Disease Related Dementias
9Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD
10Amyloid
11Amyloid beta
12Amyloid beta-Peptides - genetics
13Amyloid beta-Peptides - metabolism
14Animal
15Animals
16Article
17Basic Medicine
18Behavioral
19Biological Sciences
20Biologiska vetenskaper
21Brain
22Brain - metabolism
23Brain - pathology
24Brain Disorders
25Cognition
26Cognition - physiology
27Dementia
28Disease Models
29Disease Models, Animal
30endogenous factors
31Female
32Frontotemporal Lobar Degeneration
33Frontotemporal Lobar Degeneration - genetics
34Frontotemporal Lobar Degeneration - metabolism
35Frontotemporal Lobar Degeneration - therapy
36Gene Expression Regulation
37Granulins
38Health Sciences
39Humans
40Immunity
41Immunity, Innate - physiology
42Immunology
43Inbred C57BL
44Innate
45Intercellular Signaling Peptides
46Intercellular Signaling Peptides and Proteins - deficiency
47Intercellular Signaling Peptides and Proteins - genetics
48Intercellular Signaling Peptides and Proteins - metabolism
49Knockout
50Male
51Medical
52Medical and Health Sciences
53Medicin och hälsovetenskap
54Medicinska och farmaceutiska grundvetenskaper
55Mice
56Mice, Inbred C57BL
57Mice, Knockout
58Mice, Transgenic
59Microglia
60Microglia - metabolism
61Microglia - pathology
62Natural Sciences
63Naturvetenskap
64Neurodegenerative
65Neurological
66Neurosciences
67Neurovetenskaper
68Peptides
69Phagocytosis
70Plaque
71Plaque, Amyloid - metabolism
72Plaque, Amyloid - pathology
73Progranulins
74Proteins
75Rats
76Regulation
77Social Science
78Transgenic
79Up-Regulation
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1Min, Sang-Won
2Krabbe, Grietje
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4Zhou, Yungui
5Asgarov, Rustam
6Li, Yaqiao
7Martens, Lauren H
8Elia, Lisa P
9Ward, Michael E
10Mucke, Lennart
11Farese, Jr, Robert V
12Gan, Li
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4Zhou, Yungui
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6Li, Yaqiao
7Martens, Lauren H
8Elia, Lisa P
9Ward, Michael E
10Mucke, Lennart
11Farese, Jr, Robert V
12Gan, Li
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abstractHaploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
copUnited States
pubeScholarship, University of California
pmid25261995
doi10.1038/nm.3672
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