Independent Generation of Amyloid-β via NovelAPPTranscripts Article Swipe
Emil K. Gustavsson
,
Emily K. Abel
,
Hannah Macpherson
,
Gunnar Brinkmalm
,
Diana Piotrowska
,
Aaron Z. Wagen
,
Kylie Montgomery
,
Claudio Villegas-Llerena
,
Tatiana A. Giovannucci
,
Rohan de Silva
,
Amanda Heslegrave
,
Nick C. Fox
,
Henrik Zetterberg
,
Henry Houlden
,
John Hardy
,
Selina Wray
,
Charles Arber
,
Mina Ryten
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.13.651054
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.13.651054
The amyloid precursor protein ( APP ) is processed by multiple enzymes to generate biologically active peptides, including amyloid-β (Aβ), which aggregates to form the hallmark pathology of Alzheimer’s disease (AD). Aβ is produced through an initial β-secretase cleavage of APP, generating a 99-amino acid C-terminal fragment (APP-C99). Subsequent cleavage of APP-C99 by γ-secretase produces Aβ peptides of varying lengths. To better understand the transcriptional regulation of Aβ production, we employed long-read RNA sequencing and identified previously unannotated transcripts encoding APP-C99 with an additional methionine residue (APP-C100), generated independently of β-secretase cleavage. These transcripts are expressed separately from full-length APP , and we observed that cells lacking full-length APP can still produce Aβ through these shorter isoforms. Importantly, mass spectrometry analysis of cerebrospinal fluid (CSF) revealed peptides consistent with the methionine-extended Aβ species, supporting the in vivo translation of these transcripts. Our findings reveal an alternative pathway for Aβ generation and aggregation, highlighting a potential new target for modulating Aβ accumulation in AD.
Related Topics
Concepts
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.05.13.651054
- https://www.biorxiv.org/content/biorxiv/early/2025/05/14/2025.05.13.651054.full.pdf
- OA Status
- green
- References
- 56
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4410362411
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4410362411Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1101/2025.05.13.651054Digital Object Identifier
- Title
-
Independent Generation of Amyloid-β via NovelAPPTranscriptsWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-05-14Full publication date if available
- Authors
-
Emil K. Gustavsson, Emily K. Abel, Hannah Macpherson, Gunnar Brinkmalm, Diana Piotrowska, Aaron Z. Wagen, Kylie Montgomery, Claudio Villegas-Llerena, Tatiana A. Giovannucci, Rohan de Silva, Amanda Heslegrave, Nick C. Fox, Henrik Zetterberg, Henry Houlden, John Hardy, Selina Wray, Charles Arber, Mina RytenList of authors in order
- Landing page
-
https://doi.org/10.1101/2025.05.13.651054Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2025/05/14/2025.05.13.651054.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2025/05/14/2025.05.13.651054.full.pdfDirect OA link when available
- Concepts
-
Amyloid (mycology), Amyloid precursor protein, Chemistry, Computer science, Computational biology, Biology, Medicine, Internal medicine, Alzheimer's disease, Disease, Inorganic chemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
0Total citation count in OpenAlex
- References (count)
-
56Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2046847750, https://openalex.org/W1963680576, https://openalex.org/W2096410114, https://openalex.org/W2081881251, https://openalex.org/W4221113970, https://openalex.org/W2030892371, https://openalex.org/W1779570864, https://openalex.org/W1988986946, https://openalex.org/W2906336433, https://openalex.org/W2103440561, https://openalex.org/W2133019124, https://openalex.org/W2139595777, https://openalex.org/W3047278342, https://openalex.org/W4225741213, https://openalex.org/W3152692563, https://openalex.org/W4384522480, https://openalex.org/W3137826907, https://openalex.org/W1978677685, https://openalex.org/W2069682857, https://openalex.org/W2041214001, https://openalex.org/W2037851765, https://openalex.org/W2147029696, https://openalex.org/W1969271586, https://openalex.org/W2018303840, https://openalex.org/W1928655587, https://openalex.org/W4398209174, https://openalex.org/W4289638000, https://openalex.org/W3214124483, https://openalex.org/W4376876239, https://openalex.org/W4400033871, https://openalex.org/W4399213038, https://openalex.org/W2030165834, https://openalex.org/W3173932013, https://openalex.org/W3006757803, https://openalex.org/W1986223165, https://openalex.org/W3199353075, https://openalex.org/W4220673357, https://openalex.org/W4401055811, https://openalex.org/W2035690272, https://openalex.org/W2061123524, https://openalex.org/W4390570791, https://openalex.org/W2147718170, https://openalex.org/W2937299859, https://openalex.org/W2023652080, https://openalex.org/W2618231866, https://openalex.org/W2572710398, https://openalex.org/W2890074452, https://openalex.org/W2789843538, https://openalex.org/W2108234281, https://openalex.org/W4393004003, https://openalex.org/W4283511977, https://openalex.org/W2990427812, https://openalex.org/W2125636389, https://openalex.org/W1807758003, https://openalex.org/W2940842830, https://openalex.org/W2917579965 |
| referenced_works_count | 56 |
| abstract_inverted_index.( | 5 |
| abstract_inverted_index.) | 7 |
| abstract_inverted_index., | 101 |
| abstract_inverted_index.a | 43, 154 |
| abstract_inverted_index.To | 61 |
| abstract_inverted_index.an | 36, 83, 145 |
| abstract_inverted_index.by | 10, 53 |
| abstract_inverted_index.in | 136, 162 |
| abstract_inverted_index.is | 8, 33 |
| abstract_inverted_index.of | 28, 40, 51, 58, 67, 90, 122, 139 |
| abstract_inverted_index.to | 13, 23 |
| abstract_inverted_index.we | 70, 103 |
| abstract_inverted_index.AD. | 163 |
| abstract_inverted_index.APP | 6, 100, 109 |
| abstract_inverted_index.Aβ | 32, 56, 68, 113, 132, 149, 160 |
| abstract_inverted_index.Our | 142 |
| abstract_inverted_index.RNA | 73 |
| abstract_inverted_index.The | 1 |
| abstract_inverted_index.and | 75, 102, 151 |
| abstract_inverted_index.are | 95 |
| abstract_inverted_index.can | 110 |
| abstract_inverted_index.for | 148, 158 |
| abstract_inverted_index.new | 156 |
| abstract_inverted_index.the | 25, 64, 130, 135 |
| abstract_inverted_index.APP, | 41 |
| abstract_inverted_index.acid | 45 |
| abstract_inverted_index.form | 24 |
| abstract_inverted_index.from | 98 |
| abstract_inverted_index.mass | 119 |
| abstract_inverted_index.that | 105 |
| abstract_inverted_index.vivo | 137 |
| abstract_inverted_index.with | 82, 129 |
| abstract_inverted_index.(AD). | 31 |
| abstract_inverted_index.(CSF) | 125 |
| abstract_inverted_index.These | 93 |
| abstract_inverted_index.cells | 106 |
| abstract_inverted_index.fluid | 124 |
| abstract_inverted_index.still | 111 |
| abstract_inverted_index.these | 115, 140 |
| abstract_inverted_index.which | 21 |
| abstract_inverted_index.(Aβ), | 20 |
| abstract_inverted_index.active | 16 |
| abstract_inverted_index.better | 62 |
| abstract_inverted_index.reveal | 144 |
| abstract_inverted_index.target | 157 |
| abstract_inverted_index.APP-C99 | 52, 81 |
| abstract_inverted_index.amyloid | 2 |
| abstract_inverted_index.disease | 30 |
| abstract_inverted_index.enzymes | 12 |
| abstract_inverted_index.initial | 37 |
| abstract_inverted_index.lacking | 107 |
| abstract_inverted_index.pathway | 147 |
| abstract_inverted_index.produce | 112 |
| abstract_inverted_index.protein | 4 |
| abstract_inverted_index.residue | 86 |
| abstract_inverted_index.shorter | 116 |
| abstract_inverted_index.through | 35, 114 |
| abstract_inverted_index.varying | 59 |
| abstract_inverted_index.99-amino | 44 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.analysis | 121 |
| abstract_inverted_index.cleavage | 39, 50 |
| abstract_inverted_index.employed | 71 |
| abstract_inverted_index.encoding | 80 |
| abstract_inverted_index.findings | 143 |
| abstract_inverted_index.fragment | 47 |
| abstract_inverted_index.generate | 14 |
| abstract_inverted_index.hallmark | 26 |
| abstract_inverted_index.lengths. | 60 |
| abstract_inverted_index.multiple | 11 |
| abstract_inverted_index.observed | 104 |
| abstract_inverted_index.peptides | 57, 127 |
| abstract_inverted_index.produced | 34 |
| abstract_inverted_index.produces | 55 |
| abstract_inverted_index.revealed | 126 |
| abstract_inverted_index.species, | 133 |
| abstract_inverted_index.cleavage. | 92 |
| abstract_inverted_index.expressed | 96 |
| abstract_inverted_index.generated | 88 |
| abstract_inverted_index.including | 18 |
| abstract_inverted_index.isoforms. | 117 |
| abstract_inverted_index.long-read | 72 |
| abstract_inverted_index.pathology | 27 |
| abstract_inverted_index.peptides, | 17 |
| abstract_inverted_index.potential | 155 |
| abstract_inverted_index.precursor | 3 |
| abstract_inverted_index.processed | 9 |
| abstract_inverted_index.(APP-C99). | 48 |
| abstract_inverted_index.C-terminal | 46 |
| abstract_inverted_index.Subsequent | 49 |
| abstract_inverted_index.additional | 84 |
| abstract_inverted_index.aggregates | 22 |
| abstract_inverted_index.amyloid-β | 19 |
| abstract_inverted_index.consistent | 128 |
| abstract_inverted_index.generating | 42 |
| abstract_inverted_index.generation | 150 |
| abstract_inverted_index.identified | 76 |
| abstract_inverted_index.methionine | 85 |
| abstract_inverted_index.modulating | 159 |
| abstract_inverted_index.previously | 77 |
| abstract_inverted_index.regulation | 66 |
| abstract_inverted_index.separately | 97 |
| abstract_inverted_index.sequencing | 74 |
| abstract_inverted_index.supporting | 134 |
| abstract_inverted_index.understand | 63 |
| abstract_inverted_index.(APP-C100), | 87 |
| abstract_inverted_index.alternative | 146 |
| abstract_inverted_index.full-length | 99, 108 |
| abstract_inverted_index.production, | 69 |
| abstract_inverted_index.transcripts | 79, 94 |
| abstract_inverted_index.translation | 138 |
| abstract_inverted_index.unannotated | 78 |
| abstract_inverted_index.Importantly, | 118 |
| abstract_inverted_index.accumulation | 161 |
| abstract_inverted_index.aggregation, | 152 |
| abstract_inverted_index.biologically | 15 |
| abstract_inverted_index.highlighting | 153 |
| abstract_inverted_index.spectrometry | 120 |
| abstract_inverted_index.transcripts. | 141 |
| abstract_inverted_index.β-secretase | 38, 91 |
| abstract_inverted_index.γ-secretase | 54 |
| abstract_inverted_index.Alzheimer’s | 29 |
| abstract_inverted_index.cerebrospinal | 123 |
| abstract_inverted_index.independently | 89 |
| abstract_inverted_index.transcriptional | 65 |
| abstract_inverted_index.methionine-extended | 131 |
| cited_by_percentile_year | |
| countries_distinct_count | 0 |
| institutions_distinct_count | 18 |
| citation_normalized_percentile.value | 0.2247628 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |