CD33 in Alzheimer’s Disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review

Abstract

Alzheimer’s disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

“…to alpha2-3-or alpha2-6-linked sialic acids by human but not mouse CD33, [96] and in intracellular CD33 signaling motifs [e.g. two immunotyrosine inhibitory motifs (ITIMs) present in human but not mouse CD33 [97,98]. Moreover, predictions based on increased CD33 expression and increased plaque burden in human AD brains [99,100] were not at first glance completely consistent with the outcomes of experiments that reduced CD33 expression in knockout mice and BV2 murine microglia, which resulted in impaired uptake and clearance of Aβ42 in cultured microglia and reduced plaque burden and insoluble Aβ42 in APP/PS1/CD33 −/− mice [95].…”

The role of innate immunity in Alzheimer's disease

“…For instance, CD33, also known as Siglec-3, is another microglial 80,81 In addition, sialic acids decorate the glycoproteins and glycolipids found in Aβ plaques, and can therefore stimulate CD33 signaling in the AD brain. 80 However, in contrast to TREM2, which signals utilizing ITAMs, CD33…”

“…has intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). 80 The phosphorylation of ITIMs promotes the docking of Src homology 2 domain-containing phosphatases (SHPs) to inhibit downstream microglial signaling mediated by ITAMs that would have otherwise led to the removal of Aβ in the brain parenchyma. 80 The CD33 rs3865444 C AD risk allele leads to increased CD33 receptor expression, which results in impaired Aβ42 phagocytosis.…”

“…80 The phosphorylation of ITIMs promotes the docking of Src homology 2 domain-containing phosphatases (SHPs) to inhibit downstream microglial signaling mediated by ITAMs that would have otherwise led to the removal of Aβ in the brain parenchyma. 80 The CD33 rs3865444 C AD risk allele leads to increased CD33 receptor expression, which results in impaired Aβ42 phagocytosis. 82 Increased expression of CD33 is significantly associated with a higher clinical score in AD patients and elevated AD pathology.…”

The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

“…Great interest has revolved around this protein since its identification as a genetic risk factor for AD in genome-wide association studies [ 92 ]. CD33 interacts with Aβ selectively through its extracellular sialic-binding domain [ 93 ]. The deletion of the specific CD33 mRNA exon coding for the sialic-binding domain of the protein was in fact associated with a decreased risk for AD [ 94 ].…”