| 21. |
- Johansson, Kalle, et al.
(författare)
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Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study
- 2022
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Ingår i: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS. Methods: We evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS >= 4) and MS-NoFatigue (MS-NoF, FSS < 4). Results: MS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis. Conclusion: Although the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients.
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| 22. |
- Lantero Rodriguez, Juan, et al.
(författare)
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Tau protein profiling in tauopathies: a human brain study
- 2024
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Ingår i: MOLECULAR NEURODEGENERATION. - 1750-1326. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal accumulation of misfolded and hyperphosphorylated tau protein in brain is the defining feature of several neurodegenerative diseases called tauopathies, including Alzheimer's disease (AD). In AD, this pathological change is reflected by highly specific cerebrospinal fluid (CSF) tau biomarkers, including both phosphorylated and non-phosphorylated variants. Interestingly, despite tau pathology being at the core of all tauopathies, CSF tau biomarkers remain unchanged in certain tauopathies, e.g., progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal neurodegeneration (CBD). To better understand commonalities and differences between tauopathies, we report a multiplex assay combining immunoprecipitation and high-resolution mass spectrometry capable of detecting and quantifying peptides from different tau protein isoforms as well as non-phosphorylated and phosphorylated peptides, including those carrying multiple phosphorylations. We investigated the tau proteoforms in soluble and insoluble fractions of brain tissue from subjects with autopsy-confirmed tauopathies, including sporadic AD (n = 10), PSP (n = 11), PiD (n = 10), and CBD (n = 10), and controls (n = 10). Our results demonstrate that non-phosphorylated tau profiles differ across tauopathies, generally showing high abundance of microtubule-binding region (MTBR)-containing peptides in insoluble protein fractions compared with controls; the AD group showed 12-72 times higher levels of MTBR-containing aggregates. Quantification of tau isoforms showed the 3R being more abundant in PiD and the 4R isoform being more abundant in CBD and PSP in the insoluble fraction. Twenty-three different phosphorylated peptides were quantified. Most phosphorylated peptides were measurable in all investigated tauopathies. All phosphorylated peptides were significantly increased in AD insoluble fraction. However, doubly and triply phosphorylated peptides were significantly increased in AD even in the soluble fraction. Results were replicated using a validation cohort comprising AD (n = 10), CBD (n = 10), and controls (n = 10). Our study demonstrates that abnormal levels of phosphorylation and aggregation do indeed occur in non-AD tauopathies, however, both appear pronouncedly increased in AD, becoming a distinctive characteristic of AD pathology.
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| 23. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease
- 2021
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed. Method Solid-phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross-sectional studies including AD (n = 52) and controls (n = 37). Results Increased concentrations of beta-synuclein, gamma-synuclein, neurogranin, phosphatidylethanolamine-binding protein 1, and 14-3-3 proteins were observed in AD patients compared to controls, while neuronal pentraxin-2 and neuronal pentraxin receptor were decreased. Discussion We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.
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| 24. |
- Portelius, Erik, 1977, et al.
(författare)
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A novel pathway for amyloid precursor protein processing.
- 2011
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:6, s. 1090-98
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) can be proteolytically processed along two pathways, the amyloidogenic that leads to the formation of the 40-42 amino acid long Alzheimer-associated amyloid beta (Abeta) peptide and the non-amyloidogenic in which APP is cut in the middle of the Abeta domain thus precluding Abeta formation. Using immunoprecipitation and mass spectrometry we have shown that Abeta is present in cerebrospinal fluid (CSF) as several shorter isoforms in addition to Abeta1-40 and Abeta1-42. To address the question by which processing pathways these shorter isoforms arise, we have developed a cell model that accurately reflects the Abeta isoform pattern in CSF. Using this model, we determined changes in the Abeta isoform pattern induced by alpha-, beta-, and gamma-secretase inhibitor treatment. All isoforms longer than and including Abeta1-17 were gamma-secretase dependent whereas shorter isoforms were gamma-secretase independent. These shorter isoforms, including Abeta1-14 and Abeta1-15, were reduced by treatment with alpha- and beta-secretase inhibitors, which suggests the existence of a third and previously unknown APP processing pathway involving concerted cleavages of APP by alpha- and beta-secretase.
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| 25. |
- Portelius, Erik, 1977, et al.
(författare)
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An Alzheimer's disease-specific beta-amyloid fragment signature in cerebrospinal fluid.
- 2006
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Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 409:3, s. 215-9
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of the neurotoxic beta-amyloid peptide (Abeta), especially the 42 amino acid peptide Abeta1-42. While much is known about the production of Abeta1-42, many questions remain about how the peptide is degraded. To investigate the degradation pattern, we developed a method based on immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry that determines the Abeta degradation fragment pattern in cerebrospinal fluid (CSF). We found in total 18 C-terminally and 2 N-terminally truncated Abeta peptides and preliminary data indicated that there were differences in the detected Abeta relative abundance pattern between AD and healthy controls. Here, we provide direct evidence that an Abeta fragment signature consisting of Abeta1-16, Abeta1-33, Abeta1-39, and Abeta1-42 in CSF distinguishes sporadic AD patients from non-demented controls with an overall accuracy of 86%.
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| 26. |
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| 27. |
- Portelius, Erik, 1977, et al.
(författare)
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Characterization of tau in cerebrospinal fluid using mass spectrometry.
- 2008
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Ingår i: Journal of proteome research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 7:5, s. 2114-20
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Tidskriftsartikel (refereegranskat)abstract
- The neurodegenerative disorder Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The presence of neurofibrillary tangles, consisting of hyperphosphorylated tau protein, is one of the major neuropathologic characteristics of the disease, making this protein an attractive biomarker for AD and a possible target for therapy. Here, we describe an optimized immunoprecipitation mass spectrometry method that enables, for the first time, detailed characterization of tau in human cerebrospinal fluid. The identities of putative tau fragments were confirmed using nanoflow liquid chromatography and tandem mass spectrometry. Nineteen tryptic fragments of tau were detected, of which 16 are found in all tau isoforms while 3 represented unique tau isoforms. These results pave the way for clinical CSF studies on the tauopathies.
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| 28. |
- Portelius, Erik, 1977, et al.
(författare)
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Effects of gamma-Secretase Inhibition on the Amyloid beta Isoform Pattern in a Mouse Model of Alzheimer's Disease.
- 2009
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Ingår i: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 6:5-6
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Tidskriftsartikel (refereegranskat)abstract
- Background:Accumulation of amyloid beta (Abeta) in the brain is believed to represent one of the earliest events in the Alzheimer disease process. Abeta is generated from amyloid precursor protein after sequential cleavage by beta- and gamma-secretase. Alternatively, alpha-secretase cleaves within the Abeta sequence, thus, precluding the formation of Abeta. A lot of research has focused on Abeta production, while less is known about the non-amyloidogenic pathway. We have previously shown that Abeta is present in human cerebrospinal fluid (CSF) as several shorter C-terminal truncated isoforms (e.g. Abeta1-15 and Abeta1-16), and that the levels of these shorter isoforms are elevated in media from cells that have been treated with gamma-secretase inhibitors. Objective:To explore the effect of N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase-inhibitor, treatment on the Abeta isoform pattern in brain tissue and CSF from Tg2576 mice. Methods: Immunoprecipitation using the anti-Abeta antibodies 6E10 and 4G8 was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. Results: All fragments longer than and including Abeta1-17 displayed a tendency towards decreased levels upon gamma-secretase inhibition, whereas Abeta1-15 and Abeta1-16 indicated slightly elevated levels during treatment. Conclusion: These data suggest that Abeta1-15 and Abeta1-16 may be generated through a third metabolic pathway independent of gamma-secretase, and that these Abeta isoforms may serve as biomarkers for secretase inhibitor treatment.
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| 29. |
- Portelius, Erik, 1977, et al.
(författare)
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Identification of novel APP/Abeta isoforms in human cerebrospinal fluid.
- 2009
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Ingår i: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 6:3, s. 87-94
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aggregation of beta-amyloid (Abeta) into oligomers and plaques is the central pathogenic mechanism in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein (APP) by beta- and gamma-secretases, whereas, in the nonamyloidogenic pathway, alpha-secretase cleaves within the Abeta sequence, and thus precludes Abeta formation. A lot of research has focused on Abeta production and the neurotoxic 42-amino-acid form of Abeta (Abeta1-42), while less is known about the nonamyloidogenic pathway and how Abeta is degraded. OBJECTIVE: To study the Abeta metabolism in man by searching for novel Abeta peptides in cerebrospinal fluid (CSF). METHODS: Immunoprecipitation, using an anti-Abeta antibody, 6E10, was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. RESULTS: We identified 12 truncated APP/Abeta peptides in the CSF, all of which end at amino acid 15 in the Abeta sequence, i.e. 1 amino acid before the proposed alpha-secretase site. Of these 12 APP/Abeta peptides, 11 are novel peptides and start N-terminally of the beta-secretase site. The most abundant APP/Abeta peptide starts 25 amino acids before the beta-secretase site, APP/Abeta (-25 to 15), and had a concentration of approximately 80 pg/ml. The identity of all the APP/Abeta peptides was verified in a cohort of AD patients and controls. A first pilot study also showed that the intensity of several APP/Abeta peaks in CSF was higher in AD cases than in controls. CONCLUSION: These data suggest an enzymatic activity that cleaves the precursor protein in a specific manner that may reflect a novel metabolic pathway for APP and Abeta.
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| 30. |
- Portelius, Erik, 1977, et al.
(författare)
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Identification of novel N-terminal fragments of amyloid precursor protein in cerebrospinal fluid.
- 2010
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Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 223:2, s. 351-358
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. Two pathological hallmarks in the brain of AD patients are neurofibrillary tangles and senile plaques. The plaques consist mainly of beta-amyloid (Abeta) peptides that are produced from the amyloid precursor protein (APP), by sequential cleavage by beta- and gamma-secretase. Most previous studies have been focused on the C-terminal fragments of APP, where the Abeta sequence is localized. The purpose of this study was to search for N-terminal fragments of APP in cerebrospinal fluid (CSF) using mass spectrometry (MS). By using immunoprecipitation (IP) combined with matrix-assisted laser desorption/ionization time-of-flight MS as well as nanoflow liquid chromatography coupled to high resolution tandem MS we were able to detect and identify six novel N-terminal APP fragments [APP((18-119)), APP((18-121)), APP((18-122)), APP((18-123)), APP((18-124)) and APP((18-126))], having molecular masses of approximately 12 kDa. The presence of these APP derivatives in CSF was also verified by Western blot analysis. Two pilot studies using either IP-MS or Western blot analysis indicated slightly elevated levels of N-terminal APP fragments in CSF from AD patients compared with controls, which are in need of replications in independent and larger patient materials.
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