Available online 5 August 2022, 101111

Alzheimer's disease (AD) is the most common form of neurodegenerative disease and is considered the main cause of dementia worldwide. Genome-wide association studies combined with integrated analysis of functional datasets support a critical role for microglia in AD pathogenesis, identifying them as important potential therapeutic targets. The ability of immunomodulatory receptors on microglia to control the response to pathogenic amyloid-β aggregates has gained significant interest. Siglec-3, also known as CD33, is one of these immunomodulatory receptors expressed on microglia that has been identified as an AD susceptibility factor. Here, we review recent advances made in understanding the multifaceted roles that CD33 plays in microglia with emphasis on two human-specific CD33 isoforms that differentially correlate with AD susceptibility. We also describe several different therapeutic approaches for targeting CD33 that have been advanced for the purpose of skewing microglial cell responses.

CD33

Alzheimer's disease (AD)

Microglia

Siglecs

Genome-wide association studies

Single nucleotide polymorphism

murine/mouse CD33 protein

The long isoform of CD33 protein

The short isoform of CD33 protein

Immunoreceptor tyrosine-based inhibitory motif

Immunoreceptor tyrosine-based activatory motif

Triggering receptor expressed on myeloid cells 2

Disease associated mciroglia

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