SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease

Brinkmalm, Ann; Brinkmalm, Gunnar; Honer, William G.; Frölich, Lutz; Hausner, Lucrezia; Minthon, Lennart; Hansson, Oskar; Wallin, Anders; Zetterberg, Henrik; Blennow, Kaj; Öhrfelt, Annika

doi:10.1186/1750-1326-9-53

Cited by 235 publications

(225 citation statements)

References 40 publications

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“…Another advantage of our study is the relatively large number of cases with DLB and PDD, giving us more potential to mitigate the influence of the individual changes that occur in smaller cohorts. One limitation of our study is that our AD cohort was comprised of only 18 cases, however our results are in agreement with previous findings regarding SNAP25 as a promising biomarker for synapse degeneration in AD [41]. The availability of longitudinal standardized clinical data in brain bank studies is a relatively unique feature of our study though longitudinal MMSE scores were not available for all patients (Supplementary Table 1).…”

Section: Discussionsupporting

confidence: 73%

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Bereczki

Francis

Howlett

et al. 2016

Alzheimer's & Dementia

141

109

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METHODS: 129 post-mortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphological changes and cognitive decline.RESULTS: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. DISCUSSION: Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

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Section: Discussionsupporting

confidence: 73%

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Bereczki

Francis

Howlett

et al. 2016

Alzheimer's & Dementia

141

109

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“…It is therefore an important presynaptic marker of functional synapses. Consistent with the idea that early AD and cognitive impairment are highly correlated with synaptic dysfunction, SNAP25 was found to be decreased in the membrane-associated fractions derived from the brains of AD patients, whereas increased levels were observed in the CSF of early AD patients compared with normal control patients (60). These results suggest that SNAP25 is a good candidate biomarker for cognitive decline.…”

supporting

confidence: 79%

“…Several lines of evidence support the idea that A␤ oligomers are toxic to synapses and cells including proteomic studies (36,40,60,61,74). It has been proposed that A␤ oligomers interact with membrane receptors and the membrane itself to increase calcium and lipid peroxidation (14).…”

mentioning

confidence: 90%

“…These include Rab3A, synaptotagmin, SNAP25, and neurogranin (59). Of these, SNAP25 and neurogranin were validated as biomarkers for synaptic degeneration in AD in studies using immunoaffinity purification coupled with MS detection (60,61). The synaptosomal-associated protein 25 (SNAP25) mediates synaptic communication by mediating the fusion of synaptic vesicles with the plasma membrane.…”

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confidence: 99%

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Neurodegeneration and Alzheimer's disease (AD). What Can Proteomics Tell Us About the Alzheimer's Brain?

Moya-Alvarado

Gershoni-Emek

Perlson

et al. 2016

Molecular & Cellular Proteomics

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Neurodegenerative diseases, such as Alzheimers diseases (AD), are becoming more prevalent as the population ages. However, the mechanisms that lead to synapse destabilization and neuron death remain elusive. The advent of proteomics has allowed for high-throughput screening methods to search for biomarkers that could lead to early diagnosis and treatment and to identify alterations in the cellular proteome that could provide insight into disease etiology and possible treatment avenues. In this review, we have concentrated mainly on the findings that are related to how and whether proteomics studies have contributed to two aspects of AD research, the development of biomarkers for clinical diagnostics, and the recognition of proteins that can help elucidate the pathways leading to AD brain pathology. Neurodegenerative diseases are becoming more prevalent as the population ages, yet the mechanisms that lead to synapse destabilization and neuronal death remain elusive. The advent of proteomics has led to methods for highthroughput screening to search for biomarkers that can be used for the early diagnosis and treatment of various diseases and to identify alterations in the cellular proteome that can provide insight into disease etiology and potential avenues for treatment. How and why only specific classes of neurons are affected when a genetic mutation is identified in a ubiquitously expressed gene are major questions that underlie the study of neurodegeneration. Clear examples of this phenomenon are the mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1) and 2 (PSEN2) that occur in Alzheimer's disease (AD) 1 , which affect learning and memory circuits (1, 2); super oxide dismutase 1 (SOD1) mutations that specifically affect motor neurons (MNs) in amyotrophic lateral sclerosis (3); huntingtin mutations that affect cortico-striatal circuits in cases of Huntington's disease (4, 5) and Parkin and Pink1 mutations associated with autosomal recessive familial early-onset Parkinson disease targeting dopamine generating cells in the substantia nigra (6, 7).All the neurodegenerative diseases mentioned above are characterized by neuronal dysfunction and neuronal death. However, they are distinct in terms of their genetics, pathologies, phenotypes, and treatments. Proteomics studies have been performed to analyze differentially expressed proteins in different disease paradigms, however, the diversity of models and samples that have been included in these studies are too numerous to cover in a review. We have therefore focused mainly on studies performed in AD because it is the most prevalent neurodegenerative disorder (8) and a larger number of studies have been performed using similar biological samples. Thus, in this review, we have concentrated mainly on findings related to how and whether proteomics studies have contributed to the identification of biomarkers or to our understanding of brain pathology in AD.AD is a multifactorial and complex neurodegenerative disorder that is characterized by progressive ...

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“…Based on this, it is conceivable that SEPT8 could play a central role at the synaptic level in the early stages of Alzheimer's-disease-related synaptotoxicity. It has been recently shown that protein affinity purification combined with mass spectrometry can be utilized for the identification of fragments of the presynaptic SNARE complex component synaptosomal-associated protein 25 (SNAP25) in the cerebrospinal fluid (Brinkmalm et al, 2014). Indeed, significantly increased levels of SNAP25 fragments have been observed in the cerebrospinal fluid of Alzheimer's disease patients even by the very early stages of the disease.…”

Section: Discussionmentioning

confidence: 99%

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Kurkinen

Marttinen

Turner

et al. 2016

Journal of Cell Science

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Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a posttranslational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer'sdisease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

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SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease

Cited by 235 publications

References 40 publications

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Neurodegeneration and Alzheimer's disease (AD). What Can Proteomics Tell Us About the Alzheimer's Brain?

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

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