Ersity (2012TS114 to Dr. JP.S) as well as the grants from the National Institutes of Well being (HL095556 and HL108922 to Y.H). The authors declare no conflict of interest.AbbreviationsSTEP ERK pNPP PTP KIM KIS Striatal-enriched tyrosine phosphatases Extracellular signal-regulated protein kinase Para-nitrophenyl phosphate Protein tyrosine phosphatase Kinase interaction motif Kinase-specific sequenceJ Neurochem. Author manuscript; readily available in PMC 2015 January 01.Li et al.Page
The American Journal of Pathology, Vol. 183, No. 3, Septemberajp.amjpathol.orgNEUROBIOLOGYAPOE3, but Not APOE4, Bone Marrow Transplantation Mitigates Behavioral and Pathological Adjustments inside a Mouse Model of Alzheimer DiseaseYue Yang, Eiron Cudaback, Nikolas L. Jorstad, Jake F. Hemingway, Catherine E. Hagan, Erica J. Melief, Xianwu Li, Tom Yoo, Shawn B. Khademi, Kathleen S. Montine, Thomas J. Montine, and C. Dirk KeeneFrom the Division of Pathology, University of Washington, Seattle, Washington Accepted for publication May perhaps 24, 2013. Address correspondence to C. Dirk Keene, M.D., Ph.D., Harborview Health-related Center, Box 359791, 325 Ninth Ave, Seattle, WA 98104. E-mail: [email protected] E4 (APOE4) genotype may be the strongest genetic danger aspect for late-onset Alzheimer disease and confers a proinflammatory, neurotoxic phenotype to microglia. Here, we tested the hypothesis that bone marrow cell APOE genotype modulates pathological progression in experimental Alzheimer illness. We performed bone marrow transplants (BMT) from green fluorescent proteineexpressing human APOE3/ three or APOE4/4 donor mice into lethally irradiated 5-month-old APPswe/PS1DE9 mice. Eight months later, APOE4/4 BMTerecipient APPswe/PS1DE9 mice had drastically impaired spatial working memory and increased detergent-soluble and plaque Ab compared with APOE3/3 BMTerecipient APPswe/PS1DE9 mice.1633667-60-3 Chemscene BMT-derived microglia engraftment was considerably decreased in APOE4/4 recipients, who also had correspondingly much less cerebral apoE.6-Bromo-5-fluoroisoquinolin-1(2H)-one In stock Gene expression analysis in cerebral cortex of APOE3/3 BMT recipients showed lowered expression of tumor necrosis factor-a and macrophage migration inhibitory aspect (each neurotoxic cytokines) and elevated immunomodulatory IL-10 expression in APOE3/3 recipients compared with these that received APOE4/4 bone marrow.PMID:27108903 This was not due to detectable APOE-specific variations in expression of microglial key histocompatibility complex class II, C-C chemokine receptor (CCR) kind 1, CCR2, CX3C chemokine receptor 1 (CX3CR1), or C5a anaphylatoxin chemotactic receptor (C5aR). Collectively, these findings suggest that BMT-derived APOE3-expressing cells are superior to those that express APOE4 in their ability to mitigate the behavioral and neuropathological changes in experimental Alzheimer disease. (Am J Pathol 2013, 183: 905e917; http://dx.doi.org/10.1016/j.ajpath.2013.05.009)Humans uniquely have three various apolipoprotein E (APOE ) alleles (2, three, and four). APOE4 would be the single greatest genetic threat aspect for late-onset Alzheimer illness (AD), and there is a gene dosage impact.1 Nevertheless, genetic association does not inform function/pathogenesis. Many mechanisms have been postulated that predominantly focus on production, metabolism, or clearance of amyloid-b (Ab) and that happen to be variably supported by various observations, like: i) APOE genotype is strongly related to Ab levels in brain and cerebrospinal fluid of AD patients2,three; ii) modulation of apolipoprotein E (apoE) protein levels in.
