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Aims: The aggregation and deposition of amyloid-β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length Aβ peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated Aβ4-x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated Aβ peptides., Methods: We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples., Results: In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the Aβ peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated Aβ-6-x and Aβ-3-x peptides, of which the latter serve as a component in a promising Aβ-based plasma biomarker. Aβ-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated Aβ-6/-3-x peptides., Discussion: The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD., (© 2024 The Author(s). Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Background: In Canada, disparities between Indigenous and non-Indigenous Peoples continue to exist in health and education because of the past and current harms of racism and colonization. One step towards closing health gaps is clinicians who can provide health and social care services that are free of racism and mistrust. Indigenous health providers are in the best position to provide this culturally relevant and safe care to their own communities. Therefore, more Indigenous students graduating from health professional programs are required to meet these needs. Indigenous identity support can be a facilitator for Indigenous student academic success but developing one's Indigenous identity can be challenging in post-secondary education environments. We explored how Indigenous rehabilitation students expressed, and wanted to be supported in their identity and academic success., Methods: Using a narrative inquiry approach, we conducted interviews with seven students from the occupational, physical, and respiratory therapy programs of a Canadian university. Students were asked to tell their story of learning about, applying to, and being in their rehabilitation program and how their Indigenous identity impacted these experiences. Data analysis was conducted by Indigenous and non-Indigenous team members, analyzing the stories on interaction of the participant with (1) themselves and others, (2) time, and (3) situation or place., Results: The researchers developed seven mini-stories, one for each participant, to illustrate the variation between participant experiences in the development of their Indigenous and professional identity, before and during their rehabilitation program. The students appreciated the opportunities afforded to them by being admitted to their programs in a Indigenous Peoples category, including identity affirmation. However, for most students, being in this category came with feared and/or experienced stigma. The work to develop a health professional identity brought even more complexity to the already complex work of developing and maintaining an Indigenous identity in the colonized university environment., Conclusion: This study highlights the complexity of developing a rehabilitation professional identity as an Indigenous student. The participant stories call for universities to transform into an environment where Indigenous students can be fully accepted for their unique gifts and the identities given to them at birth., (© 2024. The Author(s).)