Identification of a dysfunctional microglial population in human Alzheimer’s disease cortex using novel single-cell histology image analysis

Acta Neuropathologica Communications

Mike Dragunow¹  Leon C. D. Smyth²  Emma L. Scotter³  Clinton Turner⁴  Richard L. M. Faull⁵  Maurice A. Curtis⁵  Helen C. Murray⁵  Brigid Ryan⁵  Molly E. V. Swanson⁶ 

[1] Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Department of Pathology and Biomedical Science, Centre for Free Radical Research, University of Otago, 2 Riccarton Avenue, 8011, Christchurch, New Zealand;Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand;Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;

关键词: Microglia;    Alzheimer’s disease;    Tau;    Amyloid beta;    Dysfunction;    Immunohistochemistry;    Single-cell analysis;   

DOI  :  10.1186/s40478-020-01047-9

来源: Springer

【 摘 要 】

In Alzheimer’s disease (AD), microglia are affected by disease processes, but may also drive pathogenesis. AD pathology-associated microglial populations have been identified with single-cell RNA-Seq, but have not been validated in human brain tissue with anatomical context. Here, we quantified myeloid cell markers to identify changes in AD pathology-associated microglial populations. We performed fluorescent immunohistochemistry on normal (n = 8) and AD (n = 8) middle temporal gyri, co-labelling the pan-myeloid cell marker, Iba1, with one of 11 markers of interest (MOIs): CD45, HLA-DR, CD14, CD74, CD33, CD206, CD32, CD163, P2RY12, TMEM119, L-Ferritin. Novel image analyses quantified the single-cell abundance of Iba1 and each MOI. Each cell was gated into one Iba1-MOI population (Iba1low MOIhigh, Iba1high MOIhigh, or Iba1high MOIlow) and the abundance of each population was compared between AD and control. Triple-labelling of L-Ferritin and Iba1 with a subset of MOIs was performed to investigate L-Ferritin-MOI co-expression on Iba1low cells. Iba1low MOIhigh myeloid cell populations delineated by MOIs CD45, HLA-DR, CD14, CD74, CD33, CD32, and L-Ferritin were increased in AD. Further investigation of the Iba1low MOIhigh populations revealed that their abundances correlated with tau, but not amyloid beta, load in AD. The Iba1low microglial population highly expressed L-Ferritin, reflecting microglial dysfunction. The L-Ferritinhigh CD74high HLA-DRhigh phenotype of the Iba1low population mirrors that of a human AD pathology-associated microglial subpopulation previously identified using single-cell RNA-Seq. Our high-throughput immunohistochemical data with anatomical context support the microglial dysfunction hypothesis of AD.

【 授权许可】

CC BY