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 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 pathological mechanisms is still unclear, so the goal of this study was to investigate if the rs3865444 polymorphism affects development of AD pathology and the expression of CD33 mRNA and protein. For this study, we utilized DNA from 96 non-demented (ND) and 97 AD neuropathologically diagnosed cases to identify the different rs3865444 alleles and correlate with different measures of AD pathology. Using semi-quantitative histological 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 (Aβ) peptide and a range of other inflammatory activating agents resulted in reduced CD33 mRNA and protein levels.

Myeloid Cells in Alzheimer's Disease: Culprits, Victims or Innocent Bystanders?

“…The CD33 SNP rs3865444 C was associated with increased CD33 expression, leading to an accumulation of amyloid pathology as measured by Pittsburgh compound B (PiB) positive imaging signal [73]. This is in agreement with the finding that increased expression of CD33 mRNA was associated with accelerating AD pathology in cortical brain samples [74]. By contrast, another study reported reduced CD33 expression in CD33 SNP rs3865444 carriers [75], but CD33 inactivation promoted Ab uptake by microglia and mitigated Ab plaque deposition in CD33 knockout animals when crossed with an APP transgenic mouse [75].…”

The Alzheimer's disease–protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool

“…Several genome-wide association studies found that alleles of CD33 influence the risk of late-onset Alzheimer's disease (LOAD) (7)(8)(9)(10). LOAD is a human disease that impairs the cognitive function of post-reproductive individuals, and other primates do not appear to be susceptible (11)(12)(13).…”

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

“…One integrative functional genomics report followed up on the immune system gene CD33 , which was previously implicated in AD through GWAS [113, 114], by demonstrating SNP-associated changes in CD33 expression (protein), phagocytic performance of CD33-expressing monocytes (cellular function), and amyloid accumulation measured by PET imaging (brain pathology) [55]. It is notable that CD33 is expressed selectively in microglia in AD brain tissue [115], is a modulator of microglial activation, and also constitutes a druggable target that has been investigated in acute myeloid leukemia and very recently in AD [116]. Another example, discussed in Section 3.3.7, used GWAS to discover a novel association of the pro-apoptotic gene FASTKD2 with better episodic memory performance and subsequently related the memory-associated SNP to lower FASTKD2 mRNA expression (transcript), lower CSF levels of fas-mediated apoptotic factors (protein), and higher hippocampal volume and grey matter density (brain structure) [80].…”