Grants and Contracts Details
Description
Elucidating the mechanism whereby genetics impact the risk of Alzheimer’s disease (AD) is a
critical barrier to progress in translating genetics to pharmacologic strategies. A polymorphism
near CD33 has been identified as an AD risk factor in multiple genome wide association studies,
including very recent large studies. CD33 is a member of the sialic acid-binding
immunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity.
We and others have found that CD33 expression is restricted to microglia in the brain.
Moreover, the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) at
the expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain, we
interpreted the finding that loss of exon 2 was associated with decreased AD risk as meaning
that a decrease in functional CD33 and its associated immune suppression was AD-protective.
However, this interpretation needs to be reconsidered given our recent finding that CD33
abrogation due to a 4 bp CD33 genetic deletion is not associated with AD risk. In summary, we
currently propose a model wherein the D2-CD33 isoform represents a gain of function variant to
reduce AD risk because (i) a genetic polymorphism that reduces AD risk acts to increase D2-
CD33 at the expense of “full-length” CD33 but (ii) a CD33 indel that essentially deletes cell
surface CD33 does not affect AD risk. To test this model, we propose the following Specific
Aims. Specific Aim 1: Evaluate whether changes in CD33-related gene expression may
compensate for CD33 deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization
under conditions of physiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-
CD33 interactomes. Specific Aim 4: Determine impact of D2-CD33 on cellular functions critical
to microglia. Successful completion of these studies will pinpoint D2-CD33 as the primary
pharmacologic target in this locus to reduce AD risk.
Status | Finished |
---|---|
Effective start/end date | 9/30/20 → 8/31/24 |
Funding
- National Institute on Aging: $420,750.00
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