DOI: 10.1002/alz.075564 ISSN: 1552-5260

ASO‐mediated downregulation of Amyloid Precursor Protein: a new avenue for AD treatment?

Rebcca M C Gabriele, Charles Arber, Henrik Zetterberg, Emily Abel, Nick C Fox, Sarah Jolly, Paul Whiting, Hien Zhao, Selina Wray
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Mutations in the APP, PSEN1 and PSEN2 genes are causative of familial AD (fAD) and lead to accelerated cerebral amyloid beta (Aβ) accumulation. This finding led to the development of the amyloid cascade hypothesis which proposed that the aberrant production of Aβ peptides triggers a cascade of events that ultimately leads to neurodegeneration and clinical Alzheimer’s disease. Synthetic antisense oligonucleotides (ASOs) are small molecules that modify gene expression at the RNA level. We investigated the effect of ASO‐mediated APP downregulation in induced pluripotent stem cell derived neurons from individuals with fAD mutations in APP and PSEN1 to determine whether this approach can rescue disease‐associated phenotypes or Aβ processing defects.


iPSC with PSEN1 Int4del and R278I mutations, and APP duplication were differentiated into cortical neurons before treatment with ASOs targeting APP or non‐targeting controls. APP downregulation was assessed at the RNA level using qPCR and protein level by western blot. The impact of APP downregulation was assessed utilising a triplex ELISA to measure Ab38/40/42 and immunocytochemistry with antibodies against Rab5 and LAMP1 to assess the endolysosomal system.


ASO treatment led to a dose‐dependent downregulation of APP, both at the RNA and protein levels. Downregulation was stable over 3 weeks following ASO administration. This resulted in a significant reduction in the absolute levels of each Aβ species measured, although the Ab42/40 ratio was unchanged.


Considering the central role of Aβ in AD pathology, it is reasonable to believe that the downregulation of APP could be a successful therapeutic approach. ASO‐mediated APP downregulation was efficient and stable, highlighting the potential of this approach. Although the Aβ ratio was unchanged following APP downregulation, the absolute value of each Aβ species was significantly reduced, and so we hypothesise that lower levels of total Ab may reduce its harmful effects. Future work will determine the impact of reducing Ab levels on downstream cellular dysfunction, including endosome/lysosome defects.

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