title: APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease.
abstract: Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid β (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP(-/-)) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP(-/-) cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP(-/-) mice compared with wild-type mice. The mAPP(-/-) mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aβ plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease.
  
  
  
  A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid β (Aβ) peptide within plaques robustly invested with reactive microglia. This supports the notion that Aβ stimulation of microglial activation is one source of brain inflammatory changes during disease. Aβ is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Aβ are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Aβ production to drive the microgliosis associated with AD brains.
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Gunjan D
authors: 0000-0003-4488-6627
authors: GD
authors: Manocha
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Angela M
authors: AM
authors: Floden
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Keiko
authors: 0000-0001-7146-9787
authors: K
authors: Rausch
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Joshua A
authors: 0000-0002-8055-1894
authors: JA
authors: Kulas
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Brett A
authors: 0000-0003-3146-9699
authors: BA
authors: McGregor
authors: Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, 30000 Thailand.
authors: Lalida
authors: L
authors: Rojanathammanee
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Kelley R
authors: 0000-0002-2155-8877
authors: KR
authors: Puig
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: Kendra L
authors: KL
authors: Puig
authors: Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri 63121-4400, and.
authors: Sanjib
authors: 0000-0003-2189-9329
authors: S
authors: Karki
authors: Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri 63121-4400, and.
authors: Michael R
authors: MR
authors: Nichols
authors: Department of Biology, University of North Dakota, Grand Forks, North Dakota 58202.
authors: Diane C
authors: 0000-0001-5567-1889
authors: DC
authors: Darland
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors: James E
authors: JE
authors: Porter
authors: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, colin.combs@med.und.edu.
authors: Colin K
authors: CK
authors: Combs
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D060172:Morpholinos / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D060172:Morpholinos; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; amyloid precursor protein; amyloid β oligomers; microglia; neuroinflammation