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
AU - Rademakers, Rosa
AU - Weintraub, Sandra
AU - Mesulam, Marek Marsel
AU - Xia, Haibin
AU - Bigio, Eileen H.
N1 - Publisher Copyright:
© 2017 American Association of Neuropathologists, Inc. All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
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
C2 - 29044416
AN - SCOPUS:85032155045
SN - 0022-3069
VL - 76
SP - 957
EP - 968
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 11
ER -