Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

Hark, Timothy J.; Rao, Nalini R.; Castillon, Charlotte; Basta, Tamara; Smukowski, Samuel N.; Bao, Huan; Upadhyay, Arun; Bomba-Warczak, Ewa; Nomura, Toshihiro; O’Toole, Eileen; Morgan, Garry; Ali, Laith; Saito, Takashi; Guillermier, Christelle; Saido, Takaomi C.; Steinhauser, Matthew L.; Stowell, Michael H. B.; Chapman, Edwin; Contractor, Anis; Savas, Jeffrey N.

doi:10.1016/j.cels.2020.11.007

Cited by 45 publications

(101 citation statements)

References 106 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding of decreases in module 2 synaptic proteins in ALS is consistent with previous work in ALS, but differs from Alzheimer's disease, in which increases in levels of synaptic proteins in CSF have been observed (Dayon et al, 2018;Portelius et al, 2018;Higginbotham et al, 2020). It is possible that the low levels observed in ALS reflect synaptic loss, whilst in Alzheimer's they indicate an active process within synapses and alterations in synaptic protein turnover (Hark et al, 2021).…”

Section: Discussionsupporting

confidence: 88%

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS

Thompson

Charles

et al. 2021

Front. Neurosci.

View full text Add to dashboard Cite

BackgroundAmyotrophic lateral sclerosis is a clinical syndrome with complex biological determinants, but which in most cases is characterized by TDP-43 pathology. The identification in CSF of a protein signature of TDP-43 network dysfunction would have the potential to inform the identification of new biomarkers and therapeutic targets.MethodsWe compared CSF proteomic data from patients with ALS (n = 41), Parkinson’s disease (n = 19) and healthy control participants (n = 20). Weighted correlation network analysis was used to identify modules within the CSF protein network and combined with gene ontology enrichment analysis to functionally annotate module proteins. Analysis of module eigenproteins and differential correlation analysis of the CSF protein network was used to compare ALS and Parkinson’s disease protein co-correlation with healthy controls. In order to monitor temporal changes in the CSF proteome, we performed longitudinal analysis of the CSF proteome in a subset of ALS patients.ResultsWeighted correlation network analysis identified 10 modules, including those enriched for terms involved in gene expression including nucleic acid binding, RNA metabolism and translation; humoral immune system function, including complement pathways; membrane proteins, axonal outgrowth and adherence; and glutamatergic synapses. Immune system module eigenproteins were increased in ALS, whilst axonal module eigenproteins were decreased in ALS. The 19 altered protein correlations in ALS were enriched for gene expression (OR 3.05, p = 0.017) and membrane protein modules (OR 17.48, p = 0.011), including intramodular hub proteins previously identified as TDP-43 interactors. Proteins decreasing over longitudinal analysis ALS were enriched in glutamatergic synapse and axonal outgrowth modules. Protein correlation network disruptions in Parkinson’s disease showed no module enrichment.ConclusionsAlterations in the co-correlation network in CSF samples identified a set of pathways known to be associated with TDP-43 dysfunction in the pathogenesis of ALS, with important implications for therapeutic targeting and biomarker development.

show abstract

Section: Discussionsupporting

confidence: 88%

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS

Thompson

Charles

et al. 2021

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…2, B to F). The absence of unlabeled A peptides in plaques of these labeled animals verifies that starting labeling at week <7 allows for in time, metabolic introduction of 15 N to cover the plaque onset period from before A plaque deposition.…”

Section: Stable Isotopes Can Be Metabolically Incorporated In Specific A Peptides and Accumulate Into Extracellular Plaques Upon Amyloidmentioning

confidence: 61%

“…These results show that the general iSILK labeling and analysis paradigm proved suitable to generate metabolically labeled A that deposited in extracellular A plaques. The data show that initiation of 15 N feeding right before the onset of A plaque pathology is sufficient to achieve 15 N labeling of all the A peptides present in extracellular A plaques. Moreover, complementary structural imaging identified morphological heterogenous amyloid structures within the A plaques, i.e., plaque core and periphery (fig.…”

Section: Stable Isotopes Can Be Metabolically Incorporated In Specific A Peptides and Accumulate Into Extracellular Plaques Upon Amyloidmentioning

confidence: 84%

“…The results show that 15 N-labeled amino acids are incorporated into APP and A and deposit within A plaques upon plaque formation (Fig. 1E).…”

Section: Stable Isotopes Can Be Metabolically Incorporated In Specific A Peptides and Accumulate Into Extracellular Plaques Upon Amyloidmentioning

confidence: 88%

“…A major observation for the first experiments showed differences in the degree of labeling of the detected A peptides across the plaque structure. MALDI-IMS showed that the relative intensity of total 15 N-A1-42 signal was highest in the center of A plaques on June 27, 2021 http://advances.sciencemag.org/ Downloaded from Fig. 1.…”

Section: Stable Isotopes Can Be Metabolically Incorporated In Specific A Peptides and Accumulate Into Extracellular Plaques Upon Amyloidmentioning

confidence: 97%

See 2 more Smart Citations

Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

et al. 2021

View full text Add to dashboard Cite

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

show abstract

Subcellular proteomics insights into Alzheimer's disease development

Liang,

Zhuang,

Cao

et al. 2023

Proteomics Clinical Apps

View full text Add to dashboard Cite

Alzheimer's disease (AD), one of the most common dementias, is a neurodegenerative disease characterized by cognitive impairment and decreased judgment function. The expected number of AD patient is increasing in the context of the world's advancing medical care and increasing human life expectancy. Since current molecular mechanism studies on AD pathogenesis are incomplete, there is no specific and effective therapeutic agent. Mass spectrometry (MS)‐based unbiased proteomics studies provide an effective and comprehensive approach. Many advances have been made in the study of the mechanism, diagnostic markers, and drug targets of AD using proteomics. This paper focus on subcellular level studies, reviews studies using proteomics to study AD‐associated mitochondrial dysfunction, synaptic, and myelin damage, the protein composition of amyloid plaques (APs) and neurofibrillary tangles (NFTs), changes in tissue extracellular vehicles (EVs) and exosome proteome, and the protein changes in ribosomes and lysosomes. The methods of sample separation and preparation and proteomic analysis as well as the main findings of these studies are involved. The results of these proteomics studies provide insights into the pathogenesis of AD and provide theoretical resource and direction for future research in AD, helping to identify new biomarkers and drugs targets for AD.

show abstract

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

Cited by 45 publications

References 106 publications

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS

Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

Subcellular proteomics insights into Alzheimer's disease development

Contact Info

Product

Resources

About