Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization.
Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-β42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.
Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Mailpoint 806, Southampton General Hospital, Southampton SO16 6YD, UK.
Elina
E
Zotova
Viraj
V
Bharambe
Matthew
M
Cheaveau
William
W
Morgan
Clive
C
Holmes
Scott
S
Harris
James W
JW
Neal
Seth
S
Love
James A R
JA
Nicoll
Delphine
D
Boche
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins; D015922:Complement C1q / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D051116:Receptors, Scavenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D014611:Vaccination / Q000379:methods*; D016875:tau Proteins / Q000378:metabolism
C112986:AIF1 protein, human; D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D008840:Microfilament Proteins; D010446:Peptide Fragments; D051116:Receptors, Scavenger; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D015922:Complement C1q
Alzheimer’s disease; clinical trial; innate immunity; microglia, immunotherapy