Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer's Disease.

This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating ^® (CDR ^® ). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR ^® . Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.
Competing Interests: RJB is the Director of the DIAN-TU and Principal Investigator of DIAN and the DIAN-TU-001 trial. Unrelated to this study, for the DIAN-TU, he receives research support from the NIA, Eli Lilly and Company, F. Hoffman-La Roche, Ltd., Eisai, Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active Members: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech). JH is a paid consultant/advisor for Parabon Nanolabs, Roche, Prothena, and AlzPath. GYRH reports no competing interests directly relevant to this work. He has received grants or contracts from CIHR, NIA/NIH, has been a clinical trials investigator supported by Biogen, Cassava, and Lilly, has participated in expert advisory committee supported by Biogen, Roche, and NovoNordisk, and is the current president of C5R (Consortium of Canadian Centres for Clinical Cognitive Research). EMM receives Grant Funding from NIA; Institutional funding from Eli Lilly, Hoffmann-La Roche, Eisai. He is a DSMB member (paid directly) for Alector; Eli Lilly; a Scientific Advisory Board Member (paid directly to me) for Alzamend, Fondation Alzheimer. He acts as a Consultant/Advisor for Sage Therapeutics, Eli Lilly, Sanofi, AstraZeneca,Hoffmann La-Roche. CC has received research support from GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Circular Genomics and owns stocks in these companies. DP is an employee of GlaxoSmithKline (GSK) and holds stock in GSK. CX is supported by National Institute on Aging (NIA) grants R01 AG067505 and R01 AG053550. All other authors have nothing to disclose. JCM is the Friedman Distinguished Professor of Neurology, Associate Director, Knight ADRC; Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276; and U19 AG024904. Neither he nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. TLSB has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, and F. Hoffmann-La Roche, Ltd. She also serves as an unpaid consultant to Eisai and Siemensand is on the Speaker’s Bureau for Biogen. AER reports no competing interests. He receives research support for this work from the National Institute on Aging (R01AG053267, U19AG032438) TI reports no competing interests. He received research support for this work from AMED (JP23dk0207066 and JP23dk0207049). GSD reports no competing interests directly relevant to this work. His research is supported by NIH (K23AG064029, U01AG057195, U01NS120901, U19AG032438). He serves as a consultant for Parabon Nanolabs Inc and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Amgen Pharmaceuticals, and a consultant for Arialys Therapeutics. He has developed educational materials for PeerView Media, Inc, and Continuing Education Inc. He owns stock in ANI pharmaceuticals. Dr. Day’s institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in-kind contributions of radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). RJP is Neuropathology Core Leader for the DIAN observational study and the DIAN Trials Unit. He receives research support for this work from the National Institute on Aging (U19 AG032438, U19AG032438-09S1, R01AG068319). His laboratory receives cost recovery funding from Biogen for tissue procurement and processing services related to ALS clinical trials. Neither he nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. FL has grants not related to this paper from NIH, DIAN, Enroll-HD and BIOGEN. JL reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve, Merck and Roche, consulting fees from Axon Neuroscience, EISAI and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. SBB receives support from the National Institute on Aging (NIA) and the Michael J Fox Foundation. All other authors have nothing to disclose.