Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration

Höglund, Kina; Schussler, Nathalie; Kvartsberg, Hlin; Smailović, Una; Brinkmalm, Gunnar; Liman, Victor; Becker, Bruno; Zetterberg, Henrik; Cedazo-Minguez, Ángel; Bateman, Randall J.; Lefevre, Isabel A.; Eyquem, Stéphanie; Hansson, Oskar; Blennow, Kaj

doi:10.1016/j.nbd.2019.104645

Cited by 19 publications

(18 citation statements)

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“…Neurogranin, SNAP-25, synaptotagmin, the neuronal calcium sensing protein VILIP-1). [110][111][112][113][114] Of these, neurogranin seems the most promising, given its specificity for AD compared to other dementias and its increase in early stages over the AD spectrum. YKL-40, a microglia/astrocyte biomarker, is a promising marker to monitor treatment effect, is especially increased in FTD, and (less) in AD.…”

Section: Csf Markersmentioning

confidence: 99%

Alzheimer's disease

et al. 2021

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EN-US" style="color: black;">In this seminar the main developments in the field of Alzheimer’s Disease (AD) are highlighted. Most recent data estimate a doubling of dementia prevalence in Europe by 2050. When prevalence estimates of AD are made on a biological, rather than a clinical definition of AD, the prevalence of biologically defined AD is three times higher than that of clinically defined AD. The biological definition based on biomarkers of Aβ and tau has been suggested for research and may enter the clinic in due course. The earliest, cellular, phase of AD includes alterations in neurons, microglia and astroglia. Neuro-inflammation,¹ alterations in the vessels, aging, dysfunction of the glymphatic system act upstream or in parallel to accumulating Aβ in this cellular disease landscape. Aβ induces the spreading of tau pathology, which is associated with the appearance of necroptosis markers in neurons displaying granulo-vacuolar degeneration. Risk of AD depends for 60-80% on heritable factors. Causative genes include PSEN 1, PSEN2, APP and Sorl1. Risk genes include one or two alleles of APOE4. GWAS studies have identified another 40 risk genes. Protective genes include APOE2, and mutations in the PLCG2 , KLOTHO and the Icelandic APP A673T genes.

Next to the established CSF markers, novel biomarkers include plasma assays for Aβ and p-tau which show great promise for clinical use. Amyloid PET is now making its way into the clinical arena, while tau-PET is established in research. Multidomain lifestyle-based prevention trials suggest cognitive benefits in subpopulations of participants with increased risk of dementia. Lifestyle factors do not directly impact AD pathology, but can still contribute to a positive outcome in individuals with AD. Promising pharmacological treatments are poised at advanced stages of testing in clinical trials and include anti-abeta, anti tau, anti-inflammatory strategies.

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Section: Csf Markersmentioning

confidence: 99%

Alzheimer's disease

et al. 2021

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Next to the established CSF markers, novel biomarkers include plasma assays for Aβ and p-tau which show great promise for clinical use. Amyloid PET is now making its way into the clinical arena, while tau-PET is established in research. Multidomain lifestyle-based prevention trials suggest cognitive benefits in subpopulations of participants with increased risk of dementia. Lifestyle factors do not directly impact AD pathology, but can still contribute to a positive outcome in individuals with AD. Promising pharmacological treatments are poised at advanced stages of testing in clinical trials and include anti-abeta, anti tau, anti-inflammatory strategies.

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“…In an effort to detect the molecular forms of Ng appearing in CSF, we analyzed pooled concentrated CSF samples on immunoblots (see Figure 2). We used two in-house generated monoclonal antibodies (mab), namely NG36 and NG2, with estimated epitopes of Ng63-77 and Ng52-63, respectively (Becker et al, 2018;Kvartsberg, Duits, et al, 2015) and the commercial NG-H6 monoclonal antibody with the previously mapped epitope estimated around Ng37-39 (Höglund et al, 2020 (Höglund et al, 2020). We have used GAP-43 monoclonal as well as polyclonal antibodies to show that GAP-43 is indeed detected at 55 kDa in TBS brain extracts (Figure S1) ; therefore, the band detected around 55 kDa with NG-H6 very likely represents GAP43…”

Section: Neurogranin Is Present In Different Molecular Forms In Csfmentioning

confidence: 99%

Molecular forms of neurogranin in cerebrospinal fluid

Nazir

Camporesi

Brinkmalm

et al. 2020

Journal of Neurochemistry

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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. K E Y W O R D S CSF, heparin-binding motif, neurograninThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Before we figure out the pathway that includes pathological molecular changes and related association, we cannot make a clear definition of the timing. CSF Ng was increased in AD compared to CN or Parkinson's disease frontotemporal dementia and amyotrophic lateral sclerosis [15][16][17].…”

Section: Introductionmentioning

confidence: 93%

“…In an animal model of AD, Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while it decreased in a brain when CSF Ng is a biomarker of synaptic degeneration [17].…”

Section: Association Of the Proteins With The Neuroimaging Findings Amentioning

confidence: 99%

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer’s Disease

Zhou

Fukushima²

2020

Preprint

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The Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, NfL and NG is the main alternation and connection to others. The neuro-inflammation, synaptic dysfunction and neuronal injury function is exhibited prior the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between the proteins that CSF SNAP-25, VILIP-1 and YKL-40 can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects are converted to AD, even with very high elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.

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Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration

Cited by 19 publications

References 50 publications

Alzheimer's disease

Alzheimer's disease

Molecular forms of neurogranin in cerebrospinal fluid

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer’s Disease

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Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration

Cited by 19 publications

References 50 publications

Alzheimer's disease

Alzheimer's disease

Molecular forms of neurogranin in cerebrospinal fluid

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer&rsquo;s Disease

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Clinical Utility of the Pathogenesis-related Proteins in Alzheimer’s Disease