Gene therapy for Alzheimer’s disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation

Abstract

Neuroinflammation is a key contributor to the pathology of Alzheimer’s Disease (ad). CD33 (Siglec-3) is a transmembrane sialic acid-binding receptor on the surface of microglial cells. CD33 is upregulated on microglial cells from post-mortem ad patient brains and high levels of CD33 inhibit uptake and clearance of amyloid beta (Aβ) in microglial cell cultures. Furthermore, knock-out of CD33 reduces amyloid plaque burden in mouse models of ad. Here, we tested whether a gene therapy strategy to reduce CD33 on microglia in ad could decrease Aβ plaque load. Intracerebroventricular injection of an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miRCD33) into APP/PS1 mice reduced CD33 mRNA and TBS-soluble Aβ40 and Aβ42 levels in brain extracts. Treatment of APP/PS1 mice with miRCD33 vector at an early age (2 months) was more effective at reducing Aβ plaque burden than intervening at later times (8 months). Furthermore, early intervention downregulated several microglial receptor transcripts (e.g. CD11c, CD47 and CD36) and pro-inflammatory activation genes (e.g. Tlr4 and Il1b). Marked reductions in the chemokine Ccl2 and the pro-inflammatory cytokine Tnfα were observed at the protein level in the brain from APP/PS1 mice treated with miRCD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knock-down strategies to reduce ad pathology.

The role of innate immune genes in Alzheimer's disease

“…Treatment of Alzheimer's disease mice with an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miR CD33 ) at an early age reduced CD33 mRNA, brain levels of TBS-soluble Aβ40 and Aβ42, and Aβ plaque burden in APP/PS1 mice. Early intervention with miR CD33 downregulated pro-inflammatory activation genes, cytokines and chemokines [ 63 ▪ ]. Collectively, we provided the first proof-of-concept that therapies targeting CD33 can reduce both Aβ accumulation and neuroinflammation.…”

Microglia Polarization in Alzheimer’s Disease: Mechanisms and a Potential Therapeutic Target

“…For example, CD33 inactivation promoted the uptake of Aβ by microglia (Griciuc et al, 2013). Consistently, CD33 knockdown significantly decreased the proinflammatory-related transcripts and Aβ plaque in AD mice at an early age (Griciuc et al, 2020). Thus, CD33 might be a potential target for AD treatment.…”

“…Consistently, the number of CD33-positive microglia markedly increased in the cortex of AD cases ( Griciuc et al, 2013 ). CD33 knockout led to the increase of inflammasome genes and anti-inflammatory gene expression in AD mice ( Griciuc et al, 2019 ), while a recent study further demonstrated that CD33 knockdown significantly decreased the pro-inflammatory-related transcripts in AD mice ( Griciuc et al, 2020 ; Figure 2 ).…”

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

“…CD33, a transmembrane sialic acid–binding receptor expressed on the surface of microglial cells, inhibits uptake and clearance of Abeta. ICV injection of an AAV vector encoding an artificial microRNA targeted against CD33 (miRCD33) in APP/PS1 mice reduced expression of pro-inflammatory genes (Tlr4, Il1b, Ccl2, and Tnfα) and amyloid beta accumulation ( Griciuc et al, 2020 ).…”