Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Duits, Flora H.; Brinkmalm, Gunnar; Teunissen, Charlotte E.; Brinkmalm, Ann; Scheltens, Philip; Flier, Wiesje M. van der; Zetterberg, Henrik; Blennow, Kaj

doi:10.1186/s13195-017-0335-x

Cited by 104 publications

(113 citation statements)

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“…Overall, despite the variable characteristics of these four modules, these results aligned well with the decreased abundance of neuronal-linked modules we have previously observed in the AD brain [10]. Furthermore, these findings support the large body of evidence implicating synaptic dysfunction and cellular hypometabolism in AD pathogenesis [34][35][36], as well as provide a global perspective on their underlying protein alterations in brain. In summary, systems-level analysis of our Brain1 proteome generated modules of protein co-expression with disease-specific alterations in AD consistent with many of our prior findings.…”

Section: Systems-based Analysis Of the Brain Proteome Reveals Modulessupporting

confidence: 87%

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Higginbotham

Ping

Dammer

et al. 2019

Preprint

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Our results used an integrative proteomic approach to identify panels of CSF AD protein biomarkers with strong links to a variety of pathological mechanisms in the diseased brain.Abstract: Alzheimer's disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

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Section: Systems-based Analysis Of the Brain Proteome Reveals Modulessupporting

confidence: 87%

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Higginbotham

Ping

Dammer

et al. 2019

Preprint

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“…Some of the proteins that we observe are reduced in AD synapses have been observed as CSF biomarkers associating with disease. For example, we observe a 25% decrease in neurexin 2 and over 30% decrease in neurogranin abundance in AD APOE 4 superior temporal gyrus compared to controls, whereas recently published biomarker studies observed increases in neurexin 2 and neurogranin in CSF of people with mild cognitive impairment or AD 36, 37, 38 . In another study of CSF, a group of 9 synaptic proteins (GluR2, GluR4, Neuroligin-2, Neurexin-3A, Neurexin-2A, Calsynytenin-1, Syntaxin-1B, Thy-1, and VAMP-2) were increased before markers of neurodegeneration are observed 39 .…”

Section: Discussioncontrasting

confidence: 76%

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Hesse

Hurtado

Jackson

et al. 2019

Preprint

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Highlights 42• Proteomic analysis of synapses isolated from Alzheimer's disease and control subject 43 brains identifies over 5,500 proteins in human synapses. 44• In silico analysis reveals region-specific decreases in proteins involved in synaptic 45 and mitochondrial function and increases in proteins involved in neuroimmune 46 signaling and intracellular signaling in AD. 47• The apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic 48 proteins in AD. 49 50 Abstract 51Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive 52 decline, and synaptic pathology contributes to disease pathophysiology. We recently 53 discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 54 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in 55 human AD brain. To begin to understand the molecular cascades involved in synapse loss in 56 AD and how this is mediated by APOE, and to generate a resource of knowledge of changes 57 in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico 58 analysis of synaptoneurosome preparations from temporal and occipital cortices of human 59 AD and control subjects with known APOE gene status. Our analysis identified over 5,500 60 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-61 associated changes in multiple molecular pathways including a decreased abundance in AD 62 of proteins important for synaptic and mitochondrial function and an increased abundance of 63 proteins involved in neuroimmune interactions and intracellular signaling. 64 65

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“…VGF has also been proposed as a biomarker of AD and its progression (42). Although CSF levels of VGF, a neuronal and neurosecretory protein, might be anticipated to decrease coincident with neuronal loss as AD progresses, it is important to note that in two biomarker studies, the CSF levels of a number of related neurosecretory and synaptic proteins, including chromogranin A, secretogranin II, 7B2, proSAAS, clusterin, neurexins 1, 2 and 3, and neuropentraxin 1 were either increased or unchanged in patients with AD compared to controls, while VGF levels consistently were reduced in AD patient CSF (41,44). Our systematic analysis of changes in gene expression and proteomic profiles in disease-free and AD brains identified VGF as not only strongly associated with AD, but as a key driver gene of our AD-associated network, a finding that is further supported by our direct perturbation of VGF in the 5xFAD mouse model.…”

Section: Discussionmentioning

confidence: 99%

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Lin²,

Wang

et al. 2018

Preprint

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Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression. One sentence summary: VGF protects against Alzheimer's diseaseAlthough VGF has been reported to regulate fear and spatial memories in mouse models (35,37,38), and to be an AD biomarker, with VGF-derived peptides found to be reduced in the CSF of AD patients compared to healthy controls (39-46), VGF has not previously been causally associated with AD. We determined through our network models that VGF was the only downregulated KD for AD that was conserved across the RNA, protein, and combined RNA and protein networks we constructed. We replicated these findings in other brain regions (47) and in an independent dataset (48,49), and observed evidence of genetic association in the largest AD GWAS to date (10). Given VGF's status as the top KD we identified in our networks, we overexpressed VGF in the 5xFAD mouse model of familial AD and found that it not only lowered overall amyloid plaque and Tau-associated dystrophic neurite levels, but it significantly perturbed gene expression traits that were enriched for genes predicted by our networks to change in response to VGF modulation. Taken together, these results provide molecular and functional validation of our multiscale causal network analysis finding of VGF as a driver of AD pathophysiology. We conclude that the genes and clinical features linked to VGF provide novel insights into the mechanisms underlying AD risk and pathogenesis.Results: Our overall strategy for elucidating the complexity of AD is depicted in Fig. 1 (Fig. S1) and is centered on the objective, data-driven construction of predictive network models of AD that can then be queried to identify network components causally associated with AD. The master regulators that modulate the state of these AD-associated network components can then be readily identified from the network model. We have previously developed and applied the network reconstruction algorithm, RIMBANET, which statistically infers causal relationships between DNA variation, gene expression, protein expression and clinical features that are scored

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Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Cited by 104 publications

References 50 publications

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

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