CSF Ubiquitin Levels Are Higher in Alzheimer’s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 4; p. 497
• Main Authors: Abu-Rumeileh, Samir, Oeckl, Patrick, Baiardi, Simone, Halbgebauer, Steffen, Steinacker, Petra, Capellari, Sabina, Otto, Markus, Parchi, Piero
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.03.2020; MDPI
• Subjects: Aged; Alzheimer Disease - cerebrospinal fluid; Alzheimer's disease; Analysis; Atomic properties; Biological markers; biomarkers; Biomarkers - cerebrospinal fluid; Brain - metabolism; Brain - pathology; Case-Control Studies; Cerebrospinal fluid proteins; chitinase-3-like protein 1; Comparative analysis; Creutzfeldt-Jakob Syndrome - cerebrospinal fluid; creutzfeldt–jakob disease; Female; Frontotemporal dementia; Frontotemporal Dementia - cerebrospinal fluid; human prion disease; Humans; Male; mass spectrometry; Measurement; Middle Aged; neurofilament ligh chain; Prion diseases; Prion Diseases - cerebrospinal fluid; Prion Diseases - pathology; Ubiquitin; Ubiquitin - cerebrospinal fluid; Ubiquitin - metabolism; Italy; human prion disease; chitinase-3-like protein 1; Alzheimer’s disease; biomarkers; frontotemporal dementia; mass spectrometry; neurofilament ligh chain; Creutzfeldt–Jakob disease; ubiquitin
• DOI: 10.3390/biom10040497
• ISSN: 2218-273X

Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD). However, to date, no study explored this biomarker across the heterogeneous spectrum of prion disease. Using a liquid chromatography−multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with prion disease (n = 84), AD (n = 38), and frontotemporal dementia (FTD) (n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits. Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median protein values similar to controls. The biomarker showed a good to optimal accuracy in the differential diagnosis between NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes, sporadic CJD VV2 demonstrated significantly higher levels of CSF ubiquitin and more numerous brain ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF ubiquitin correlated with biomarkers of neurodegeneration and astrogliosis in NDs, and was associated with disease stage but not with survival in prion disease. The differential increase of CSF free monoubiquitin in prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and neuroinflammation.