CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.

bioRxiv : the preprint server for biology 2025

Dodd RB, Enomoto M, Zhou Y, Satoh K, Zhang Y, Chen F, Acheson B, Ghaffari D, Sayn-Wittgenstein E, Manning JJ, Dukas GV, Patel R, Burguete AS, Kralovec MJ, Rashid M, Hall JL, Tamucci KA, Chatila ZK, Liu M, Lee AJ, Vardarajan BN, Taga MF, Pollari S, Rabinovitch A, Rillahan CD, Bobkov AA, Sergienko E, Meadows W, Qamar S, Randle SJ

Abstract

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimer’s disease (AD). The full-length CD33 M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and Aβ). This interaction induces CD33 M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33 M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33 MΔ4bp ).

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