Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Open accessAbstract
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.
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Microglial phagocytic capability is affected by AD risk factors such as TREM2 and CD33.
“Phagocytic capability of microglia has been shown to be affected by risk factors for AD, such as TREM2 and CD33 (Griciuc et al., 2013; Kleinberger et al., 2014).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Griciuc et al., 2013
In microglia, CD33 seems to regulate phagocytosis of amyloid-β, with a reduction in CD33 associated with increased phagocytosis.
“In microglia, CD33 seems to regulate phagocytosis of amyloid-β, with a reduction in CD33 associated with increased phagocytosis.70”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [70]
CD33 expression was shown to correlate with pan-microglial markers Iba1 or CD11b, supporting its microglial localization.
“CD33 expression was shown to correlate with pan-microglial markers Iba1 or CD11b, supporting its microglial localization.66, 70, 104”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [70]
Higher expression of CD33 genes or of CD33 immunolabelled cells was noted in three studies in the superior and middle temporal gyri, frontal cortex and temporal cortex of patients with Alzheimer's disease relative to controls.
“Higher expression of CD33 genes or of CD33 immunolabelled cells was noted in three studies in the superior and middle temporal gyri, frontal cortex and temporal cortex of patients with AD relative to controls.66, 70, 104”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [70]
The three stereology studies that counted all microglia, identified by either Iba1 or morphology, reported no differences in total microglial counts in AD relative to control samples, whereas increases were noted in the number of cells positive for activation-associated markers MHCII, CD68 and CD33.
“Interestingly, the three stereology studies that counted all microglia, identified by either Iba1 or morphology, reported no differences in total microglial counts in AD relative to control samples,54, 122, 70 whereas increases were noted in the number of cells positive for activation-associated markers MHCII, CD68 and CD33.54, 70, 83, 84”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [70]
Very few studies reported using stereology to complete their cell counts.
“Very few studies reported using stereology to complete their cell counts,54, 70, 83, 84, 122 the gold standard for quantifying cells in a tissue without bias.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [70]
CD33 inhibits Aβ uptake by microglia.
“only CD33 has been described to inhibit Aβ uptake by microglia [37].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [37]
Reactive astrocytosis and microgliosis are secondary cellular responses in diseased brain regions and may have both negative and positive effects.
“Reactive astrocytosis and microgliosis are secondary cellular responses to pathology that occur in diseased brain regions2 and may have both negative and positive effects3,4.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [4]
The rs3865444 variant reduces expression of CD33, thereby promoting protective effects potentially through CD33 downregulation.
“The rs3865444 variant was shown to reduce the expression of CD33, thereby promoting protecting effects potentially through CD33 downregulation [325].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [325]
Another CD33 variant associated with protection from Alzheimer disease is expressed at relatively low levels, reducing CD33 inhibitory potential.
“Conversely, another CD33 variant associated with protection from AD is expressed at relatively low levels, reducing CD33 inhibitory potential (138).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [138]
The CD33 genotype-phenotype relationship aligns with TREM2: TREM2 R47H reduces TREM2-ligand binding and ITAM signaling and impairs phagocytosis, whereas the CD33 variant prevents CD33-ligand interaction and presumably ITIM signaling and promotes phagocytosis.
“The CD33 genotype–phenotype relationship nicely aligns with that of TREM2: the TREM2 R47H mutation (which increases AD risk) reduces TREM2–ligand binding and ITAM signaling and impairs phagocytosis, whereas the CD33 variant (which reduces AD risk) prevents the CD33–ligand interaction and presumably ITIM signaling and promotes phagocytosis (Bradshaw et al., 2013; Griciuc et al., 2013).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Griciuc et al., 2013
Genes linked to early-onset AD risk that are expressed primarily in microglia include TREM2, MS4A, ABCA7, ApoE4, CD33, PU.1, and BIN1.
“Genetic studies show that a number of genes that have been linked to early-onset AD risk are expressed primarily in microglia.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [133]
Most GWAS loci are thought to operate by regulating the expression of neighbouring genes.
“Since most GWAS loci are thought to operate by regulating the expression of neighbouring genes (Bradshaw et al., 2013; Griciuc et al., 2013; Huang et al., 2017)”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Griciuc et al., 2013
These findings are consistent with previous work on Trem2 and CD33, suggesting these risk genes are crucial in controlling the microglial response to amyloid-induced damage.
“These findings are also consistent with previous work on Trem2 (Wang et al., 2015; Keren-Shaul et al., 2017; Mazaheri et al., 2017; Cheng-Hathaway et al., 2018; Lee et al., 2018), and CD33 (Bradshaw et al., 2013; Griciuc et al., 2013), suggesting these risk genes are crucial in controlling the microglial response to amyloid-induced damage.”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Griciuc et al., 2013
CD33 (SIGLEC3) is associated with accumulation of amyloidβ plaques in mouse Alzheimer's disease models due to diminished phagocytic capacity of microglial cells upregulating this gene.
“CD33 (SIGLEC3), a known microglial marker, is associated with the accumulation of amyloidβ plaques in mouse Alzheimer's disease models due to the diminished phagocytic capacity of microglial cells upregulating this gene 38 .”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [38]
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- Authors
- Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E.
- Affiliations
- Harvard University (US)
- Corresponding author
- Tanzi, Rudolph E.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 78
- Issue
- 4
- Pages
- 631-643
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3706457
- OpenAlex
- W2133646735
- Cited by
- 1,004
- References
- 59
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 123 · 2023: 69 · 2022: 87 · 2021: 84 · 2020: 93 · 2019: 83 · 2018: 71 · 2017: 70 · 2016: 68 · 2015: 70 · 2014: 65 · 2013: 20
- FWCI
- 51.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (5P01 AG15379, P01AG015379, AG-08487, R01AG008487, P50 AG05134, P50AG005134, T32AG000222, P30AG062421)
- National Institute of Mental Health (R01MH060009, R37MH060009)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- CD33, Alzheimer's disease, amyloid-beta 42, microglia, amyloid clearance, amyloid plaques, genetic risk factors, APP/PS1 mice, innate immunity, sialic acid-binding lectins, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Reference Values, RNA, Messenger, Case-Control Studies, Amyloid beta-Peptides, Matched-Pair Analysis, Microglia, Mice, Knockout, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mice, Sialic Acid Binding Ig-like Lectin 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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