title: Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex.
abstract: Recent findings identified the minor A allele present in the single-nucleotide polymorphism rs3865444 in the CD33 gene as being associated with the reduced risk of developing Alzheimer's disease (AD). CD33 (Siglec-3) is an immune function protein with anti-inflammatory signaling, cell adhesion, and endocytosis functions with sialic acid-modified proteins or lipids as ligands. Its involvement in AD pathologic mechanisms is still unclear; so, the goal of this study was to investigate if the rs3865444 polymorphism affects the development of AD pathology and the expression of CD33 messenger RNA (mRNA) and protein. For this study, we used DNA from 96 nondemented (ND) and 97 AD neuropathologically diagnosed cases to identify the different rs3865444 alleles and correlate with different measures of AD pathology. Using semiquantitative histologic measures of plaque and tangle pathology, we saw no significant differences between the different genotypes within these disease groups. However, increased expression of CD33 mRNA was associated with increasing AD pathology in temporal cortex brain samples. We also showed that cases with A/A alleles had reduced levels of CD33 protein in temporal cortex but increased levels of the microglia protein IBA-1. Using immunohistochemistry on temporal cortex sections, CD33 was selectively localized to microglia, with greater expression in activated microglia. The factors causing increased CD33 expression by microglia in brain are still unclear, although both genetic and disease factors are involved. Treatment of human microglia isolated from autopsy brains with amyloid-beta peptide and a range of other inflammatory activating agents resulted in reduced CD33 mRNA and protein levels.
authors.affiliation: Laboratory of Neuroinflammation, Banner Sun Health Research Institute, Sun City, AZ, USA. Electronic address: douglas.walker@bannerhealth.com.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.affiliation: Laboratory of Neuroinflammation, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Whetzel
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Geidy
authors.initials: G
authors.lastname: Serrano
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Lucia I
authors.initials: LI
authors.lastname: Sue
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Laboratory of Neuroregeneration, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Lih-Fen
authors.initials: LF
authors.lastname: Lue
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D012306:Risk; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics*
chemical_list: C112986:AIF1 protein, human; C571163:CD33 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: Amyloid beta; Cytokines; Immune signaling; Immunohistochemistry; Immunoreceptor tyrosine-based inhibitory motif; Microglia; Siglec-3; Western blot