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

Hum Mol Genet. 2020 Oct 10;29(17):2920-2935. doi: 10.1093/hmg/ddaa179.


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, knockout 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 of APP/PS1 mice treated with miRCD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knockdown strategies to reduce AD pathology. One Sentence Summary: A gene therapy approach for Alzheimer's disease using adeno-associated virus vector-based knockdown of CD33 reduced amyloid beta accumulation and neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy*
  • Humans
  • Mice
  • Mice, Transgenic / genetics
  • Microglia / metabolism
  • Microglia / pathology
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / pathology
  • Presenilin-1 / genetics*
  • Sialic Acid Binding Ig-like Lectin 3 / antagonists & inhibitors
  • Sialic Acid Binding Ig-like Lectin 3 / genetics*


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • CD33 protein, human
  • Presenilin-1
  • Sialic Acid Binding Ig-like Lectin 3