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.
Show 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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