Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging

被引：199

作者：

Bachstetter, Adam D. ^{[1
]}

Van Eldik, Linda J. ^{[1
,2
]}

Schmitt, Frederick A. ^{[1
,3
]}

Neltner, Janna H. ^{[1
,4
]}

Ighodaro, Eseosa T. ^{[1
,2
]}

Webster, Scott J. ^{[1
]}

Patel, Ela ^{[1
]}

Abner, Erin L. ^{[1
,5
]}

Kryscio, Richard J. ^{[6
,7
]}

Nelson, Peter T. ^{[1
,4
]}

机构：

[1] Univ Kentucky, Sanders Brown Ctr Aging, 800 S Limestone St, Lexington, KY 40536 USA

[2] Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA

[4] Univ Kentucky, Dept Pathol & Lab Med, Div Neuropathol, Lexington, KY USA

[5] Univ Kentucky, Dept Epidemiol, Lexington, KY USA

[6] Univ Kentucky, Dept Biostat, Lexington, KY USA

[7] Univ Kentucky, Dept Stat, Lexington, KY USA

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2015年 / 3卷

基金：

美国国家卫生研究院;

关键词：

Aging; Microglia activation; Mixed dementia; Neurodegeneration; Neuroinflammation; Neuropathology; MACROSIALIN MOUSE CD68; HEALTHY BRAIN; ACTIVATION; DYSFUNCTION; PATHOLOGY; INJURY; CELLS;

D O I：

10.1186/s40478-015-0209-z

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Introduction: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. Results: Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer's Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. Conclusions: We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes.

引用

页数：16

共 42 条

[1] Fusion of microglia with pyramidal neurons after retroviral infection [J].

Ackman, James B. ;

Siddiqi, Faez ;

Walikonis, Randall S. ;

LoTurco, Joseph J. .

JOURNAL OF NEUROSCIENCE, 2006, 26 (44) :11413-11422

[2] The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury [J].

Bachstetter, Adam D. ;

Rowe, Rachel K. ;

Kaneko, Machi ;

Goulding, Danielle ;

Lifshitz, Jonathan ;

Van Eldik, Linda J. .

JOURNAL OF NEUROSCIENCE, 2013, 33 (14) :6143-6153

[3] Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology [J].

Bachstetter, Adam D. ;

Norris, Christopher M. ;

Sompol, Pradoldej ;

Wilcock, Donna M. ;

Goulding, Danielle ;

Neltner, Janna H. ;

Clair, Daret St. ;

Watterson, D. Martin ;

Van Eldik, Linda J. .

JOURNAL OF NEUROSCIENCE, 2012, 32 (30) :10201-10210

[4] MICROGLIAL ACTIVATION IN THE INJURED AND HEALTHY BRAIN: WHAT ARE WE REALLY TALKING ABOUT? PRACTICAL AND THEORETICAL ISSUES ASSOCIATED WITH THE MEASUREMENT OF CHANGES IN MICROGLIAL MORPHOLOGY [J].

Beynon, S. B. ;

Walker, F. R. .

NEUROSCIENCE, 2012, 225 :162-171

[5] Review: Activation patterns of microglia and their identification in the human brain [J].

Boche, D. ;

Perry, V. H. ;

Nicoll, J. A. R. .

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2013, 39 (01) :3-18

[6] Identification of a unique TGF-β dependent molecular and functional signature in microglia [J].

Butovsky, Oleg ;

Jedrychowski, Mark P. ;

Moore, Craig S. ;

Cialic, Ron ;

Lanser, Amanda J. ;

Gabriely, Galina ;

Koeglsperger, Thomas ;

Dake, Ben ;

Wu, Pauline M. ;

Doykan, Camille E. ;

Fanek, Zain ;

Liu, LiPing ;

Chen, Zhuoxun ;

Rothstein, Jeffrey D. ;

Ransohoffl, Richard M. ;

Gygi, Steven P. ;

Antel, Jack P. ;

Weiner, Howard L. .

NATURE NEUROSCIENCE, 2014, 17 (01) :131-143

[7] MORPHOLOGICAL AND GENETIC ACTIVATION OF MICROGLIA AFTER DIFFUSE TRAUMATIC BRAIN INJURY IN THE RAT [J].

Cao, T. ;

Thomas, T. C. ;

Ziebell, J. M. ;

Pauly, J. R. ;

Lifshitz, J. .

NEUROSCIENCE, 2012, 225 :65-75

[8] Phagocytosis stimulates alternative glycosylation of macrosialin (mouse CD68), a macrophage-specific endosomal protein [J].

da Silva, RP ;

Gordon, S .

BIOCHEMICAL JOURNAL, 1999, 338 :687-694

[9] ATP mediates rapid microglial response to local brain injury in vivo [J].

Davalos, D ;

Grutzendler, J ;

Yang, G ;

Kim, JV ;

Zuo, Y ;

Jung, S ;

Littman, DR ;

Dustin, ML ;

Gan, WB .

NATURE NEUROSCIENCE, 2005, 8 (06) :752-758

[10]

DICKSON DW, 1994, ACTA NEUROPATHOL, V88, P212

← 1 2 3 4 5 →