Disease and region specificity of granulin immunopositivities in Alzheimer disease and frontotemporal lobar degeneration

Qinwen Mao*, Dongyang Wang, Yanqing Li, Missia Kohler, Jayson Wilson, Zachary Parton, Bella Shmaltsuyeva, Demirkan Besim Gursel, Rosa Rademakers, Sandra Weintraub, Marek-Marsel Mesulam, Haibin Xia, Eileen H Bigio

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G. In the neocortex, Grn peptide-specific immunostains were observed, for example, membranous Grn E immunopositivity in pyramidal neurons, and Grn C immunopositivity in ramified microglia. In the hippocampus, Grn immunopositivity in the CA1 and CA2 regions showed diseasespecific changes in both neurons and microglia. Most interestingly, in FTLD-TDP type A with GRN mutations, there is a 60% decrease in the density of Grn-positive microglia in the hippocampal CA1, suggesting that haploinsufficiency of the GRN mutations also extends to PGRN expression in microglia. This study provides important insights into future studies of the pathogenesis and treatment of FTLD-TDP.

Original languageEnglish (US)
Pages (from-to)957-968
Number of pages12
JournalJournal of neuropathology and experimental neurology
Volume76
Issue number11
DOIs
StatePublished - Jan 1 2017

Fingerprint

Frontotemporal Lobar Degeneration
Alzheimer Disease
TDP-43 Proteinopathies
Microglia
Haploinsufficiency
Mutation
granulin precursor protein
Peptides
Pyramidal Cells
Neocortex
Hippocampus
Monoclonal Antibodies

Keywords

  • Alzheimer disease
  • Frontotemporal lobar degeneration
  • Granulin
  • Hippocampal sclerosis
  • Microglia
  • Neuroinflammation
  • Progranulin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Mao, Qinwen ; Wang, Dongyang ; Li, Yanqing ; Kohler, Missia ; Wilson, Jayson ; Parton, Zachary ; Shmaltsuyeva, Bella ; Gursel, Demirkan Besim ; Rademakers, Rosa ; Weintraub, Sandra ; Mesulam, Marek-Marsel ; Xia, Haibin ; Bigio, Eileen H. / Disease and region specificity of granulin immunopositivities in Alzheimer disease and frontotemporal lobar degeneration. In: Journal of neuropathology and experimental neurology. 2017 ; Vol. 76, No. 11. pp. 957-968.
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abstract = "Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G. In the neocortex, Grn peptide-specific immunostains were observed, for example, membranous Grn E immunopositivity in pyramidal neurons, and Grn C immunopositivity in ramified microglia. In the hippocampus, Grn immunopositivity in the CA1 and CA2 regions showed diseasespecific changes in both neurons and microglia. Most interestingly, in FTLD-TDP type A with GRN mutations, there is a 60{\%} decrease in the density of Grn-positive microglia in the hippocampal CA1, suggesting that haploinsufficiency of the GRN mutations also extends to PGRN expression in microglia. This study provides important insights into future studies of the pathogenesis and treatment of FTLD-TDP.",
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author = "Qinwen Mao and Dongyang Wang and Yanqing Li and Missia Kohler and Jayson Wilson and Zachary Parton and Bella Shmaltsuyeva and Gursel, {Demirkan Besim} and Rosa Rademakers and Sandra Weintraub and Marek-Marsel Mesulam and Haibin Xia and Bigio, {Eileen H}",
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Disease and region specificity of granulin immunopositivities in Alzheimer disease and frontotemporal lobar degeneration. / Mao, Qinwen; Wang, Dongyang; Li, Yanqing; Kohler, Missia; Wilson, Jayson; Parton, Zachary; Shmaltsuyeva, Bella; Gursel, Demirkan Besim; Rademakers, Rosa; Weintraub, Sandra; Mesulam, Marek-Marsel; Xia, Haibin; Bigio, Eileen H.

In: Journal of neuropathology and experimental neurology, Vol. 76, No. 11, 01.01.2017, p. 957-968.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Disease and region specificity of granulin immunopositivities in Alzheimer disease and frontotemporal lobar degeneration

AU - Mao, Qinwen

AU - Wang, Dongyang

AU - Li, Yanqing

AU - Kohler, Missia

AU - Wilson, Jayson

AU - Parton, Zachary

AU - Shmaltsuyeva, Bella

AU - Gursel, Demirkan Besim

AU - Rademakers, Rosa

AU - Weintraub, Sandra

AU - Mesulam, Marek-Marsel

AU - Xia, Haibin

AU - Bigio, Eileen H

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G. In the neocortex, Grn peptide-specific immunostains were observed, for example, membranous Grn E immunopositivity in pyramidal neurons, and Grn C immunopositivity in ramified microglia. In the hippocampus, Grn immunopositivity in the CA1 and CA2 regions showed diseasespecific changes in both neurons and microglia. Most interestingly, in FTLD-TDP type A with GRN mutations, there is a 60% decrease in the density of Grn-positive microglia in the hippocampal CA1, suggesting that haploinsufficiency of the GRN mutations also extends to PGRN expression in microglia. This study provides important insights into future studies of the pathogenesis and treatment of FTLD-TDP.

AB - Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G. In the neocortex, Grn peptide-specific immunostains were observed, for example, membranous Grn E immunopositivity in pyramidal neurons, and Grn C immunopositivity in ramified microglia. In the hippocampus, Grn immunopositivity in the CA1 and CA2 regions showed diseasespecific changes in both neurons and microglia. Most interestingly, in FTLD-TDP type A with GRN mutations, there is a 60% decrease in the density of Grn-positive microglia in the hippocampal CA1, suggesting that haploinsufficiency of the GRN mutations also extends to PGRN expression in microglia. This study provides important insights into future studies of the pathogenesis and treatment of FTLD-TDP.

KW - Alzheimer disease

KW - Frontotemporal lobar degeneration

KW - Granulin

KW - Hippocampal sclerosis

KW - Microglia

KW - Neuroinflammation

KW - Progranulin

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U2 - 10.1093/jnen/nlx085

DO - 10.1093/jnen/nlx085

M3 - Article

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EP - 968

JO - Journal of Neuropathology and Experimental Neurology

JF - Journal of Neuropathology and Experimental Neurology

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