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 Gursel, Rosa V Rademakers, Sandra Weintraub, Marek Marsel Mesulam, Haibin Xia, Eileen H. Bigio

Research output: Contribution to journalArticle

9 Scopus citations

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 disease-specific 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 - Nov 1 2017

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

Fingerprint Dive into the research topics of 'Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration'. Together they form a unique fingerprint.

  • Cite this

    Mao, Q., Wang, D., Li, Y., Kohler, M., Wilson, J., Parton, Z., Shmaltsuyeva, B., Gursel, D., Rademakers, R. V., Weintraub, S., Mesulam, M. M., Xia, H., & Bigio, E. H. (2017). Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration. Journal of Neuropathology and Experimental Neurology, 76(11), 957-968. https://doi.org/10.1093/jnen/nlx085