Independent Generation of Amyloid-β via Novel APP Transcripts

Gustavsson, E. K.; Abel, E.; Macpherson, H.; Brinkmalm, G.; Piotrowska, D.; Wagen, A. Z.; Montgomery, K.; Villegas Llerena, C.; Alvarez Giovannucci, T.; de Silva, R.; Heslegrave, A.; Fox, N.; Zetterberg, H.; Houlden, H.; Hardy, J.; Wray, S.; Arber, C.; Ryten, M.

doi:10.1101/2025.05.13.651054

bioRxiv · 10.1101/2025.05.13.651054

Independent Generation of Amyloid-β via Novel APP Transcripts

Gustavsson, E. K.·Abel, E.·Macpherson, H.·Brinkmalm, G.·Piotrowska, D.·Wagen, A. Z.·Montgomery, K.·Villegas Llerena, C.·Alvarez Giovannucci, T.·de Silva, R.·Heslegrave, A.·Fox, N.·Zetterberg, H.·Houlden, H.·Hardy, J.·Wray, S.·Arber, C.·Ryten, M.

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Abstract

The amyloid precursor protein (APP) is processed by multiple enzymes to generate biologically active peptides, including amyloid-{beta} (A{beta}), which aggregates to form the hallmark pathology of Alzheimers disease (AD). A{beta} is produced through an initial {beta}-secretase cleavage of APP, generating a 99-amino acid C-terminal fragment (APP-C99). Subsequent cleavage of APP-C99 by {gamma}-secretase produces A{beta} peptides of varying lengths. To better understand the transcriptional regulation of A{beta} 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 {beta}-secretase cleavage. These transcripts are expressed separately from full-length APP, and we observed that cells lacking full-length APP can still produce A{beta} through these shorter isoforms. Importantly, mass spectrometry analysis of cerebrospinal fluid (CSF) revealed peptides consistent with the methionine-extended A{beta} species, supporting the in vivo translation of these transcripts. Our findings reveal an alternative pathway for A{beta} generation and aggregation, highlighting a potential new target for modulating A{beta} accumulation in AD.

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Gustavsson, E. K., Abel, E., Macpherson, H., Brinkmalm, G., Piotrowska, D., Wagen, A. Z., Montgomery, K., Villegas Llerena, C., Alvarez Giovannucci, T., de Silva, R., Heslegrave, A., Fox, N., Zetterberg, H., Houlden, H., Hardy, J., Wray, S., Arber, C., Ryten, M.. 2025-05-14. Independent Generation of Amyloid-β via Novel APP Transcripts. https://doi.org/10.1101/2025.05.13.651054

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