title: Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta.
abstract: The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD.
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Griciuc
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Parrado
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Lesinski
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Asselin
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.forename: Basavaraj
authors.initials: B
authors.lastname: Hooli
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Choi
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D016555:Matched-Pair Analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D063268:Sialic Acid Binding Ig-like Lectin 3