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Article ; Online: Analytical and clinical validation of a blood progranulin ELISA in frontotemporal dementias.

Meda, Francisco / Simrén, Joel / Borroni, Barbara / Cantoni, Valentina / Archetti, Silvana / Biasiotto, Giorgio / Andreasson, Ulf / Blennow, Kaj / Kvartsberg, Hlin / Zetterberg, Henrik

Clinical chemistry and laboratory medicine

2023 Volume 61, Issue 12, Page(s) 2195–2204

Abstract: Objectives: Heterozygous mutations in the granulin (: Methods: Analytical validation parameters including assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability were tested according to previously ... ...

Abstract	Objectives: Heterozygous mutations in the granulin ( Methods: Analytical validation parameters including assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability were tested according to previously described procedures. For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed Results: Among the analytical validation parameters, assay precision and repeatability were very stable (coefficients of variation <7 %). Spike recovery was 96 %, the measurement range was 6.25-400 μg/L and dilution linearity ranged from 1:50-1:200. Hemolysis did not interfere with progranulin levels, and these were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, the assay was capable of distinguishing Conclusions: In this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical laboratory practice. This easy-to-use test allows identification of potential
MeSH term(s)	Humans ; Progranulins/genetics ; Frontotemporal Dementia/diagnosis ; Frontotemporal Dementia/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; Mutation ; Enzyme-Linked Immunosorbent Assay
Chemical Substances	Progranulins ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-07-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2023-0562
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Article ; Online: Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates.

Islam, Tohidul / Kvartsberg, Hlin / Sehrawat, Anuradha / Kac, Przemysław R / Becker, Bruno / Olsson, Maria / Abrahamson, Eric E / Zetterberg, Henrik / Ikonomovic, Milos D / Blennow, Kaj / Karikari, Thomas K

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024 Volume 20, Issue 4, Page(s) 2894–2905

Abstract: Introduction: Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are ... ...

Abstract	Introduction: Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers. Methods: A homogeneous (single-antibody) immunoassay was developed using a novel anti-tau monoclonal antibody and validated with recombinant and brain tissue-derived tau. Results: The assay signals were concentration dependent for recombinant tau aggregates in solution but not monomers, and recognized peptides within, but not outside, the aggregation-prone microtubule binding region. The signals in inferior and middle frontal cortical tissue homogenates increased with neuropathologically determined Braak staging, and were higher in insoluble than soluble homogenized brain fractions. Autopsy-verified AD gave stronger signals than other neurodegenerative diseases. Discussion: The quantitative oligomer/soluble aggregate-specific assay can identify soluble tau aggregates, including oligomers, from monomers in human and in vitro biospecimens. Highlights: The aggregation of tau to form fibrils and neurofibrillary tangles is a key feature of Alzheimer's disease. However, biochemical assays for the quantification of oligomers/soluble aggregated forms of tau are lacking. We developed a new assay that preferentially binds to soluble tau aggregates, including oligomers and fibrils, versus monomers. The assay signal increased corresponding to the total protein content, Braak staging, and insolubility of the sequentially homogenized brain tissue fractions in an autopsy-verified cohort. The assay recognized tau peptides containing the microtubule binding region but not those covering the N- or C-terminal regions only.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Alzheimer Disease/metabolism ; tau Proteins/metabolism ; Neurofibrillary Tangles ; Immunoassay ; Peptides/metabolism
Chemical Substances	tau Proteins ; Peptides
Language	English
Publishing date	2024-03-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13711
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Article ; Online: Association of region-specific hippocampal reduction of neurogranin with inflammasome proteins in

Vontell, Regina T / Gober, Ryan / Dallmeier, Julian / Brzostowicki, Daniel / Barreda, Ayled / Blennow, Kaj / Zetterberg, Henrik / Kvartsberg, Hlin / Gultekin, Sakir Humayun / de Rivero Vaccari, Juan Pablo / Bramlett, Helen M / Dietrich, W Dalton / Keane, Robert W / Davis, David A / Rundek, Tatjana / Sun, Xiaoyan

Alzheimer's & dementia (New York, N. Y.)

2024 Volume 10, Issue 1, Page(s) e12444

Abstract: Introduction: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.: Methods: We investigated the protein expression, ... ...

Abstract	Introduction: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology. Methods: We investigated the protein expression, morphological differences of Ng, and correlated Ng to hyperphosphorylated tau in the Results: We show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti-ASC (IC100) positive neurons and anti-ASC positive microglia, in AD. Discussion: The finding of a negative correlation between Ng and ASC speck protein expression in Highlights: We show the role that neurogranin plays on post-synaptic signaling in specific hippocampal regions.We demonstrate that there could be clinical implications of using neurogranin as a biomarker for dementia.We describe the loss of plasticity and neuronal scaffolding proteins in the present of AD pathology.We show the response of neuroinflammation when tau proteins phosphorylate in hippocampal neurons.We show that there is a potential therapeutic target for the inflammasome, and future studies may show that IC100, a humanized monoclonal antibody directed against ASC, may slow the progression of neurodegeneration.
Language	English
Publishing date	2024-01-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12444
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Article ; Online: Neurofilament light oligomers in neurodegenerative diseases: quantification by homogeneous immunoassay in cerebrospinal fluid.

Meda, Francisco J / Knowles, Kathryn / Swift, Imogen J / Sogorb-Esteve, Aitana / Rohrer, Jonathan D / Dittrich, Anna / Skoog, Ingmar / Kern, Silke / Becker, Bruno / Blennow, Kaj / Andreasson, Ulf / Kvartsberg, Hlin / Zetterberg, Henrik

BMJ neurology open

2023 Volume 5, Issue 1, Page(s) e000395

Abstract: Background: Neurofilament light (NfL) is a widely used biomarker for neurodegeneration. NfL is prone to oligomerisation, but available assays do not reveal the exact molecular nature of the protein variant measured. The objective of this study was to ... ...

Abstract	Background: Neurofilament light (NfL) is a widely used biomarker for neurodegeneration. NfL is prone to oligomerisation, but available assays do not reveal the exact molecular nature of the protein variant measured. The objective of this study was to develop a homogeneous ELISA capable of quantifying oligomeric NfL (oNfL) in cerebrospinal fluid (CSF). Methods: A homogeneous ELISA, based on the same capture and detection antibody (NfL21), was developed and used to quantify oNfL in samples from patients with behavioural variant frontotemporal dementia (bvFTD, n=28), non-fluent variant primary progressive aphasia (nfvPPA, n=23), semantic variant PPA (svPPA, n=10), Alzheimer's disease (AD, n=20) and healthy controls (n=20). The nature of NfL in CSF, and the recombinant protein calibrator, was also characterised by size exclusion chromatography (SEC). Results: CSF concentration of oNfL was significantly higher in nfvPPA (p<0.0001) and svPPA patients (p<0.05) compared with controls. CSF oNfL concentration was also significantly higher in nfvPPA compared with bvFTD (p<0.001) and AD (p<0.01) patients. SEC data showed a peak fraction compatible with a full-length dimer (~135 kDa) in the in-house calibrator. For CSF, the peak was found in a fraction of lower molecular weight (~53 kDa), suggesting dimerisation of NfL fragments. Conclusions: The homogeneous ELISA and SEC data suggest that most of the NfL in both the calibrator and human CSF is present as a dimer. In CSF, the dimer appears to be truncated. Further studies are needed to determine its precise molecular composition.
Language	English
Publishing date	2023-02-27
Publishing country	England
Document type	Journal Article
ISSN	2632-6140
ISSN (online)	2632-6140
DOI	10.1136/bmjno-2022-000395
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Article ; Online: Neurogranin in Alzheimer's disease and ageing: A human post-mortem study.

Saunders, Tyler / Gunn, Ciaran / Blennow, Kaj / Kvartsberg, Hlin / Zetterberg, Henrik / Shenkin, Susan D / Cox, Simon R / Deary, Ian J / Smith, Colin / King, Declan / Spires-Jones, Tara

Neurobiology of disease

2023 Volume 177, Page(s) 105991

Abstract: Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and ... ...

Abstract	Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and correlate with cognition; however, few studies have focused on Ng abundance in the brain. Synapse loss in the brain correlates closely with cognitive decline in AD making synaptic biomarkers potentially important for tracking disease progression, but the links between synaptic protein changes in CSF and brain remain incompletely understood. In the current study, Ng abundance was examined in post-mortem human brain tissue across AD, healthy ageing (HA), and mid-life (ML) cohorts. Ng levels were quantified in three brain regions associated with cognitive change found during ageing and neurodegenerative diseases, namely the middle temporal gyrus, primary visual cortex and the posterior hippocampus using immunohistochemistry. To support immunohistochemical analysis, total homogenate and biochemically enriched synaptic fractions from available temporal gyrus tissues were examined by immunoblot. Finally, we examined whether Ng is associated with lifetime cognitive ageing. Ng levels were significantly reduced in AD relative to HA and ML cases across all regions. Additionally Ng was significantly reduced in HA in comparison to ML in the primary visual cortex. Immunoblotting confirms reduced Ng levels in AD cases supporting immunohistochemical results. Interestingly, there was also a significant reduction of synapse-associated Ng in our group who had lifetime cognitive decline in comparison to the group with lifetime cognitive resilience indicating loss of neurogranin in remaining synapses during ageing is associated with cognitive decline. Our findings indicate that increases in CSF Ng reflect loss of brain neurogranin and support the use of CSF Ng as a biomarker of AD and potentially of cognitive decline in healthy ageing.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Neurogranin/cerebrospinal fluid ; Cognitive Dysfunction/metabolism ; Brain/metabolism ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism
Chemical Substances	Neurogranin (132654-77-4) ; Biomarkers ; Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2023.105991
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Article ; Online: Cerebrospinal fluid N-224 tau helps discriminate Alzheimer's disease from subjective cognitive decline and other dementias.

Cicognola, Claudia / Hansson, Oskar / Scheltens, Philip / Kvartsberg, Hlin / Zetterberg, Henrik / Teunissen, Charlotte E / Blennow, Kaj

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 38

Abstract: Background: Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while ... ...

Abstract	Background: Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls. Methods: Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (Aβ42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay. Results: N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson's disease (PD, p < 0.0001), Parkinson's disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R Conclusions: N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.
MeSH term(s)	Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Biomarkers ; Cognitive Dysfunction/diagnosis ; Humans ; Peptide Fragments ; Supranuclear Palsy, Progressive ; Sweden ; tau Proteins/cerebrospinal fluid ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; MAPT protein, human ; Peptide Fragments ; tau Proteins
Language	English
Publishing date	2021-02-08
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-020-00756-6
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Article ; Online: CSF p-tau205: a biomarker of tau pathology in Alzheimer's disease.

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 12

Abstract: Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal ...

Abstract	Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (r
MeSH term(s)	Humans ; Alzheimer Disease ; Neurofibrillary Tangles ; Amyloidogenic Proteins ; Antibodies ; Biomarkers
Chemical Substances	Amyloidogenic Proteins ; Antibodies ; Biomarkers
Language	English
Publishing date	2024-01-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02659-w
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Article ; Online: Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals.

Öhrfelt, Annika / Benedet, Andréa L / Ashton, Nicholas J / Kvartsberg, Hlin / Vandijck, Manu / Weiner, Michael W / Trojanowski, John Q / Shaw, Leslie M / Zetterberg, Henrik / Blennow, Kaj

Neurology

2022 Volume 100, Issue 3, Page(s) e275–e285

Abstract: Background and objectives: To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.: Methods: In this ... ...

Abstract	Background and objectives: To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally. Methods: In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time. Results: This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n Discussion: High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; GAP-43 Protein ; Retrospective Studies ; tau Proteins ; Cognitive Dysfunction/diagnosis ; Biomarkers ; Amyloidogenic Proteins ; Atrophy ; Positron-Emission Tomography/methods ; Disease Progression
Chemical Substances	Amyloid beta-Peptides ; GAP-43 Protein ; tau Proteins ; Biomarkers ; Amyloidogenic Proteins
Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000201417
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Article ; Online: Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?

Bloniecki, Victor / Zetterberg, Henrik / Aarsland, Dag / Vannini, Patrizia / Kvartsberg, Hlin / Winblad, Bengt / Blennow, Kaj / Freund-Levi, Yvonne

Alzheimer's research & therapy

2020 Volume 12, Issue 1, Page(s) 153

Abstract: Background: The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. ... ...

Abstract	Background: The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia. Methods: A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n = 92 [61%]) were included, of which 64 had Alzheimer's disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1-42, Ng, NFL, and GAP-43. Results: No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD (n = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS. Conclusion: Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.
MeSH term(s)	Alzheimer Disease/complications ; Amyloid beta-Peptides ; Biomarkers ; Cognitive Dysfunction/etiology ; Female ; Humans ; Neurogranin ; tau Proteins
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; tau Proteins ; Neurogranin (132654-77-4)
Language	English
Publishing date	2020-11-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-020-00718-y
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Article ; Online: Molecular forms of neurogranin in cerebrospinal fluid.

Nazir, Faisal Hayat / Camporesi, Elena / Brinkmalm, Gunnar / Lashley, Tammaryn / Toomey, Christina E / Kvartsberg, Hlin / Zetterberg, Henrik / Blennow, Kaj / Becker, Bruno

Journal of neurochemistry

2020 Volume 157, Issue 3, Page(s) 816–833

Abstract: Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally ... ...

Abstract	Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally important domain, yielding the majority of fragments identified in cerebrospinal fluid (CSF), suggesting that cleavage of Ng may be a mechanism to regulate its function. Up to now, Ng has been shown to be present in CSF as both C-terminal fragments as well as full-length protein. To obtain an overview of the different molecular forms of Ng present in CSF, we show by size exclusion chromatography (SEC), immunoblotting, immunoprecipitation, and MS that Ng is present in CSF as several molecular forms. Besides monomeric full-length Ng, also higher molecular weight forms of Ng, and C-terminal- and previously not identified N-terminal fragments were observed. We found by immunodepletion that C-terminal peptides contribute on average to ~50% of the total-Ng ELISA signal in CSF samples. There were no differences in the overall C-terminal fragment/total-Ng ratios between samples from AD and control groups. In addition, we found that monomeric Ng and its C-terminal fragments bind to heparin via a heparin-binding motif, which might be of relevance for their export mechanism from neurons. Taken together, this study highlights the presence of several molecular forms of Ng in CSF, comprising monomeric full-length Ng, and N- and C-terminal truncations of Ng, as well as larger forms of still unknown composition.
MeSH term(s)	Amino Acid Sequence ; Brain Chemistry ; Chromatography, Gel ; Enzyme-Linked Immunosorbent Assay ; Heparin/metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Mass Spectrometry ; Molecular Structure ; Molecular Weight ; Neurogranin/cerebrospinal fluid ; Neurogranin/chemistry ; Protein Binding ; Ultrafiltration
Chemical Substances	NRGN protein, human ; Neurogranin (132654-77-4) ; Heparin (9005-49-6)
Language	English
Publishing date	2020-12-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15252
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