The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease

Öhrfelt, Annika; Brinkmalm, Ann; Dumurgier, Julien; Brinkmalm, Gunnar; Hansson, Oskar; Zetterberg, Henrik; Bouaziz‐Amar, Elodie; Hugon, Jacques; Paquet, Claire; Blennow, Kaj

doi:10.1186/s13195-016-0208-8

Cited by 145 publications

(117 citation statements)

References 40 publications

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“…SYT1 is a member of a synaptotagmin (syt) family, who plays a critical role in the release of neurotransmitters from presynaptic nerve terminals (Yoshihara & Montana, ). It has been reported that SYT1 was required for rapid neurotransmitter release in mouse hippocampal neurons (Evans, Ruhl, & Chapman, )and was decreased in several brain regions and increased in cerebrospinal fluid of patients with Alzheimer's disease (Ohrfelt et al, ; Yoo, Cairns, Fountoulakis, & Lubec, ). Consequently, SYT1 was selected from the predicted targets of miR‐34c for further validation in this study.…”

Section: Discussionmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

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Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.

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Section: Discussionmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

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“…Previous studies have reported elevated CSF levels of individual synaptic proteins such as neurogranin (8), SNAP-25 (9), synaptotagmin-1 (10) in AD dementia patients and neurexins 1, 2 and 3, and neurofascin (11) in prodromal AD patients. Although these findings support the idea that synaptic proteins in CSF may be informative in AD, the previously reported correlation between CSF levels of synaptic proteins with CSF levels of tau suggest that widespread neuronal loss could be a confounding factor when studying synaptic proteins in the CSF, particularly at clinical disease stages.…”

Section: Graphical Abstract Highlightsmentioning

confidence: 90%

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Lleó

Nuñez‐Llaves

Alcolea

et al. 2019

Molecular & Cellular Proteomics

143

151

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A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n ‫؍‬ 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p ‫؍‬ 0.04) in an independent cohort (n ‫؍‬ 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8fold, p < 0.04), a finding that was replicated (0.7 to 0.8fold, p < 0.05) for 6 proteins in a third cohort (n ‫؍‬ 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.

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“…; Ohrfelt et al . ). SNAP‐25 and synaptotagmin‐1 are both brain‐enriched proteins involved in vesicular trafficking.…”

Section: Biomarkers For Synaptic Degenerationmentioning

confidence: 97%

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

Brinkmalm

Portelius

Brinkmalm

et al. 2018

Journal of Neurochemistry

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Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.

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The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease

Cited by 145 publications

References 40 publications

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

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