Regular articleBRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer's disease
Introduction
Mutations in BRI2 (ITM2B) are involved in Familial British and Danish dementias (FBD and FDD, respectively) causing amyloid deposits and neurofibrillary tangles similar to those observed in Alzheimer's disease (AD) (Garringer et al., 2010, Rostagno et al., 2005, Vidal et al., 1999, Vidal et al., 2000). BRI2 is a 266 amino-acid long transmembrane type II protein (Fig. 1A) with unknown physiological function (Tsachaki et al., 2008). During maturation, BRI2 can be cleaved by a furin-like protease in its C-terminal region, which leads to the release of a 23 amino acid (AA) peptide (BRI223) (Kim et al., 1999). The remaining membrane-bound N-terminal part of BRI2 (mBRI2) contains an evolutionary conserved BRICHOS domain, which may function as a chaperone promoting the correct folding of BRI2 and preventing amyloid formation (Peng et al., 2010, Willander et al., 2011). mBRI2 can be further processed by ADAM10 and SPPL2b leading to the secretion of a 25 and 10-kDa peptides (Martin et al., 2008).
Recent studies revealed a possible link between BRI2 and the main proteins involved in AD pathogenesis, for example, amyloid β precursor protein (APP) and amyloid beta 1–40 and 1–42 (Aβ40 and Aβ42) among others. BRI223 and the BRI2 BRICHOS domain inhibited Aβ42 aggregation and delayed Aβ fibrillation in vitro and in vivo (Kim et al., 2008, Peng et al., 2010, Willander et al., 2012). Moreover, mBRI2 bound APP, leading to decreased production of Aβ40 and Aβ42 in both transgenic mice and cell cultures (Fotinopoulou et al., 2005, Matsuda et al., 2005, Matsuda et al., 2008, Matsuda et al., 2009, Matsuda et al., 2011, Tamayev and D'Adamio, 2012, Tamayev et al., 2011). In addition, BRI2 regulated the levels of the β-secretase 1 (Tsachaki et al., 2013) as well as the levels of the insulin degrading enzyme (Kilger et al., 2011); affecting the amyloidogenic processing of APP and the degradation of Aβ, respectively. Interestingly, loss of wild-type BRI2 function rather than amyloidogenesis of the mutated fragments correlated with memory deficits and impaired synaptic plasticity in FBD and FDD mice models suggesting that BRI2 has a key role in memory performance (Tamayev et al., 2010a, Tamayev et al., 2010b). Noteworthy, increased BRI2 levels prevented AD pathology in AD mice models when these were either crossed with mice expressing human BRI2 or when BRI2 was injected (Kilger et al., 2011, Kim et al., 2008, Matsuda et al., 2008). Thus, previous studies importantly related BRI2 not only with the main proteins involved in AD pathology but also with memory functioning and synaptic plasticity, which suggest that BRI2 has protective effects and that the lack of this protein leads to impaired memory and cognition.
We previously identified increased levels of BRI2 containing BRICHOS ectodomain in human cerebrospinal fluid of AD patients compared with control subjects using a hypothesis-free proteomics approach (Chiasserini et al., manuscript submitted), which further supports a link between BRI2 and AD. Taking into account the BRI2 increase observed in the cerebrospinal fluid proteomic study, the association of BRI2 with FBD and FDD, and the inhibitory effect of BRI2 on several key steps of the amyloid cascade (i.e., APP processing and Aβ aggregation), we hypothesized that BRI2 might be a relevant protein in early stages of AD pathophysiology. Thus, here we extensively analyzed the levels of BRI2 in human brain tissue from control subjects and AD patients and the relation of BRI2 with amyloid pathology. Furthermore, we studied if BRI2 protein changes in the hippocampus of AD patients were related to concentrations of its processing enzymes, including furin, ADAM10, and SPPL2b. Finally, we questioned if the binding of BRI2 to APP occurred in human tissue and if it was preserved in AD.
Section snippets
Postmortem brain tissue
Postmortem brain material was obtained from the Netherlands Brain Bank (Amsterdam, the Netherlands). All donors (n = 35) or their next of kin provided written informed consent for brain autopsy and use of tissue and medical records for research purposes. Clinical and neuropathological evaluation as well as sample processing are described in detail in Supplementary data (Methods, page 1–2). Clinical and pathologic diagnosis, gender, age, postmortem interval, and Braak and Thal scores for
Antibody characterization
Analysis of BRI2140–153 peptide using Basic Local Alignment Search Tool (NCBI) showed an e-value of 3 × 108 for BRI2. The e-values of other proteins were >0.01 indicating that BRI2140–153 is a unique sequence for human BRI2 within the BRI2-BRICHOS domain (AA 137–231). The affinity purified polyclonal antibody against BRI2140–153 detected bands of 40, 45, and 52 kDa in AD and controls human brain homogenates on Western Blots (Fig. 1B). Additional bands were detected at 15, 25, 75 kDa using
Discussion
In this study we importantly found that the levels of BRI2 containing BRICHOS domain were increased in human AD hippocampus homogenates compared with that of nondemented control subjects. We observed BRI2 deposits in the hippocampus already in early stages of the AD pathology, which were associated with Aβ plaques. Moreover, we observed that the levels of furin, ADAM10, and SPPL2b, the enzymes involved in BRI2 processing, were all modified in AD tissue. Additionally, we observed that BRI2
Disclosure statement
None of the authors with exception of Dr Scheltens have any competing interest. Dr Scheltens serves or has served on the advisory boards of: Genentech, Novartis, Pfizer, Roche, Danone, Nutricia, Jansen AI, Baxter, and Lundbeck. He has been a speaker at symposia organized by Lundbeck, Lilly, Merz, Pfizer, Jansen AI, Danone, Novartis, Roche, and Genentech. He serves on the editorial board of Alzheimer's Research & Therapy and Alzheimer's disease and Associated Disorders, is a member of the
Acknowledgements
The authors acknowledge the technical assistance of Elise S. van Haastert in the Neuropathology Laboratory at VU Medical Center, the Netherlands Brain Bank for providing human brain tissue, Dr Jenny Presto and Janne Johansson (Sweden) for antibody donation and Dr Paula Agostinho and Dr Rodrigo A. Cunha from the Center for Neuroscience and Cell Biology (Portugal) for their counsel in the immunoprecipitation experiments.
This work was supported by the Erasmus Mundus Joint Doctorate Program (EMJD
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2021, Neurobiology of DiseaseCitation Excerpt :The BRICHOS domain of ProSP-C, which is exclusively expressed in lung tissue, specifically binds to fibril surface and blocks the surface-catalyzed secondary nucleation during Aβ42 fibril formation, which leads substantial decrease in formation of toxic Aβ42 oligomers (Cohen et al., 2015; Hermansson et al., 2014; Törnquist et al., 2020). In the Central Nervous System (CNS), Bri2 is produced in neurons of the hippocampus and cortex in humans (Akiyama et al., 2004; Vidal et al., 1999), colocalizes with AD plaques (Del Campo et al., 2014; Dolfe et al., 2018), and affects the Aβ precursor protein (Aβ42PP) processing in cell models (Del Campo et al., 2014; Matsuda and Senda, 2019). In cell models the BRICHOS domain is released by proteolysis from the Bri2 precursor protein (Del Campo et al., 2014; Martin et al., 2008; Oskarsson et al., 2018).