title: Mrp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing.
abstract: Neuroinflammation plays a fundamental role in the pathogenesis of Alzheimer's disease (AD), resulting in the extensive activation of microglial and astroglial cells. Here we describe the role of myeloid-related protein Mrp14, a recently described amplifier of inflammation, in Alzheimer's disease and in the related amyloid precursor protein/presenilin1 (APP/PS1) mouse model. Detection of Mrp14 in control, mildly cognitive impaired, and AD patients revealed a strong induction of Mrp14 in protein extracts as well as in the cerebrospinal fluid, but not in blood plasma. In APP/PS1 mice, Mrp14 and its heterodimeric partner Mrp8 was found to be upregulated in microglial cells surrounding amyloid plaques. Functionally, loss of Mrp14 led to increased phagocytosis of fibrillar amyloid β (Aβ) in microglia cells in vitro and in vivo. Generating APP/PS1-transgenic mice deficient for Mrp14, we observed a decrease of key cytokines involved in APP processing, a reduction of BACE1 expression and activity, and consequently overall Aβ deposition. We therefore conclude that Mrp14 promotes APP processing and Aβ accumulation under neuroinflammatory conditions.
authors.affiliation: Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Daisy
authors.initials: D
authors.lastname: Axt
authors.forename: Angelika
authors.initials: A
authors.lastname: Griep
authors.forename: Ana
authors.initials: A
authors.lastname: Vieira-Saecker
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism* / Q000502:physiology*; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000097:blood / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology*; D008875:Middle Aged; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse