{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T01:19:27Z","timestamp":1793755167611,"version":"4.6.1"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>APP gene dosage is strongly associated with Alzheimer\u2019s disease (AD) pathogenesis. Genomic duplication of the APP locus leads to autosomal dominant early-onset AD. Individuals with Down syndrome (trisomy of chromosome 21) harbour three copies of the APP gene and invariably develop progressive AD with highly characteristic neuropathological features.<\/jats:p>\n                  <jats:p>Restoring expression of APP to the equivalent of that of two gene copies, or lower, is a rational therapeutic strategy, as it would restore physiological levels of neuronal APP protein without the potentially deleterious consequences of inadvertently inducing loss of APP function.<\/jats:p>\n                  <jats:p>Here we find that antisense oligonucleotides (ASOs) targeting APP are an effective approach to reduce APP protein levels and rescue endolysosome and autophagy dysfunction in APP duplication and Trisomy 21 human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Importantly, using ultrasensitive single-aggregate imaging techniques, we show that APP targeting ASOs significantly reduce both intracellular and extracellular amyloid-\u03b2-containing aggregates.<\/jats:p>\n                  <jats:p>Our results highlight the potential of APP ASOs as a therapeutic approach for forms of AD caused by duplication of the APP gene, including monogenic AD and AD related to Down syndrome.<\/jats:p>","DOI":"10.1093\/brain\/awae092","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T19:53:54Z","timestamp":1711050834000},"page":"2325-2333","source":"Crossref","is-referenced-by-count":43,"title":["APP antisense oligonucleotides reduce amyloid-\u03b2 aggregation and rescue endolysosomal dysfunction in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0056-7587","authenticated-orcid":false,"given":"Christy","family":"Hung","sequence":"first","affiliation":[{"name":"Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute , London NW1 1AT , UK"},{"name":"Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children , London WC1N 1DZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-5806","authenticated-orcid":false,"given":"Emre","family":"Fertan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge , Cambridge CB2 1EW , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick J","family":"Livesey","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children , London WC1N 1DZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Klenerman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge , Cambridge CB2 1EW , UK"},{"name":"UK Dementia Research Institute at University of Cambridge , Cambridge CB2 0XY , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-7675","authenticated-orcid":false,"given":"Rickie","family":"Patani","sequence":"additional","affiliation":[{"name":"Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute , London NW1 1AT , UK"},{"name":"Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London , London WC1N 3BG , 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