Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

In the paper

“Network analyses of AD brain tissue demonstrate the most reproducibility at the module level, followed by the hub protein level, and then finally at the level of precise protein connectivity rankings and module protein membership [61, 89–94].”

What the sources say

• Not checked yetcites [61] Parikshak NN, Gandal MJ, Geschwind DH. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat Rev Genet. 2015;16:441–58. source
• Not checked yetcites [89] Langfelder P, Luo R, Oldham MC, Horvath S. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7:e1001057. source
• Not checked yetcites [90] Song L, Langfelder P, Horvath S. Comparison of co-expression measures: mutual information, correlation, and model based indices. BMC Bioinforma. 2012;13:328.
• Not checked yetcites [91] Allen JD, Xie Y, Chen M, Girard L, Xiao G. Comparing statistical methods for constructing large scale gene networks. PLoS ONE. 2012;7:e29348. source
• Not checked yetcites [92] Gaiteri C, Ding Y, French B, Tseng GC, Sibille E. Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain Behav. 2014;13:13–24. source
• Not checked yetcites [93] Ballouz S, Verleyen W, Gillis J. Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics. 2015;31:2123–30. source
• Not checked yetcites [94] Marbach D, Costello JC, Kuffner R, et al. Wisdom of crowds for robust gene network inference. Nat Methods. 2012;9:796–804. source

In the paper

“Three of the modules are consistently increased in the AD brain network proteome: inflammatory, myelination, and RNA binding/splicing, while the remaining three are consistently decreased: synaptic, mitochondrial, and cytoskeleton.”

In the paper

“This module was strongly associated with wound healing and other aspects of humoral immunity and featured modest upregulation in AD dementia.”

In the paper

“A wealth of evidence suggests these proteins play a pathogenic role in disease.”

What the sources say

• Not checked yetcites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source
• Not checked yetcites [4] Julia TCW, Goate AM. Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2017;7:a024539. source
• Not checked yetcites [5] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. source

In the paper

“In addition, gene mutations that directly enhance Aβ aggregation underlie rare familial forms of the disease [4, 5].”

What the sources say

• Not checked yetcites [4] Julia TCW, Goate AM. Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2017;7:a024539. source
• Not checked yetcites [5] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. source

In the paper

“This hypothesis gained favor in the 1990s after several gene mutations directly responsible for aberrant Aβ accumulation (APP, PSEN1, PSEN2) were found to underlie rare familial forms of early-onset AD [20–22].”

What the sources say

• Not checked yetcites [20] Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Prim. 2015;1:15056. source
• Not checked yetcites [21] Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6. source
• Not checked yetcites [22] Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2:864–70. source

In the paper

“Aβ peptide is the main component of extracellular plaque pathology in the AD brain [15].”

What the sources say

• Not checked yetcites [15] Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–90. source

In the paper

“Aβ, which begins accumulating over a decade prior to clinical symptoms, comprises the cortical extracellular plaques characteristic of AD [3].”

What the sources say

• Not checked yetcites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

In the paper

“Large clinical trials of Aβ-targeting therapies have repeatedly failed, suggesting that amyloid-centric therapy is insufficient to quell disease [11].”

What the sources say

• Not checked yetcites [11] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–39. source

In the paper

“This pathogenic framework argues that the dynamic interaction of both phases is critical for disease progression and cognitive decline.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Aberrant Aβ deposition begins over a decade before the onset of clinical symptoms and spreads diffusely throughout the cerebral cortex [16, 17].”

What the sources say

• Not checked yetcites [16] Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 1999;45:358–68. source
• Not checked yetcites [17] Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019;15:888–98. source

In the paper

“Thus, some have postulated that AD maintains two pathogenic phases, including a proteopathic “biochemical” phase characterized by the direct toxic effects of Aβ and tau aggregation and a “cellular” phase encompassing a web of complex feedback and feedforward cell-mediated mechanisms that promote irreversible degeneration [12].”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Meanwhile, tau accumulation as intracellular neurofibrillary tangles (NFTs) is another hallmark feature of AD and strongly associated with progressive neuronal loss and cognitive decline [3].”

What the sources say

• Not checked yetcites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

In the paper

“However, the repeated failures of Aβ-targeting drug trials have recently bolstered critics of this hypothesis and broadened investigations of AD pathophysiology.”

What the sources say

• Not checked yetcites [11] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–39. source

In the paper

“For these reasons, a definitive AD diagnosis requires the postmortem presence of both Aβ and tau pathologies in the cerebral cortex [6].”

What the sources say

• Not checked yetcites [6] Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–62. source

In the paper

“Hyperphosphorylated tau accumulates as intraneuronal NFTs, a hallmark feature of AD pathology [3].”

What the sources say

• Not checked yetcites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

In the paper

“Thus, the hallmark proteinopathy of AD does not directly cause symptomatology but instead serves as an upstream trigger for destructive cellular processes.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Likewise, genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) in immune genes as independent risk factors for LOAD [52–55], directly implicating microglia-mediated mechanisms in sporadic AD progression.”

What the sources say

• Not checked yetcites [52] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45:1452–8. source
• Not checked yetcites [53] Lambert JC, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, et al. Implication of the immune system in Alzheimer’s disease: evidence from genome-wide pathway analysis. J Alzheimer’s Dis: JAD. 2010;20:1107–18. source
• Not checked yetcites [54] Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol. 2015;16:229–36. source
• Not checked yetcites [55] Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51. source

In the paper

“This was followed by evidence indicating that soluble oligomeric Aβ mediates synaptic dysfunction and neuronal toxicity [31–33].”

What the sources say

• Not checked yetcites [31] Benilova I, Karran E, De, Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57. source
• Not checked yetcites [32] Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9. source
• Not checked yetcites [33] Glabe CG. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging. 2006;27:570–5. source

In the paper

“It is this cellular transition, argue De Strooper and Karran, that propels the onset of cognitive symptoms.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Subsequent studies identified the locus coeruleus as the first site of pathology in AD subjects, with NFTs preceding cortical tau or Aβ deposits [41–43].”

What the sources say

• Not checked yetcites [41] Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE. Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease. Acta Neuropathologica Commun. 2017;5:8. source
• Not checked yetcites [42] Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2007;28:327–35. source
• Not checked yetcites [43] Bondareff W, Mountjoy CQ, Roth M, Rossor MN, Iversen LL, Reynolds GP, et al. Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord. 1987;1:256–62. source

In the paper

“Though the amyloid hypothesis places NFTs downstream of Aβ deposition, increasing evidence suggests that aberrant tau accumulation is a complex multifactorial process that can occur independent of amyloid.”

In the paper

“Dysfunction of the astrocytes and specialized endothelium comprising this clearance system not only contributes to increasing amyloid accumulation but also promotes irrevocable disruption of other neurovascular and glioneuronal functions, including lipid metabolism, myelin turnover, and immune regulation.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Cell-mediated feedback and feedforward mechanisms allow this dysfunction to thrive independently of accumulating amyloid and tau, precipitating chronic inflammation and circuitry imbalances that result in cell failure and death.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Compared to amyloid burden, tau levels correlate much more strongly to cognitive symptoms, suggesting a more direct link to disease progression [46].”

What the sources say

• Not checked yetcites [46] Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76:915–24. source

In the paper

“These genetic findings led to several transgenic mouse models that successfully recapitulated Aβ plaque formation, increasing support for the hypothesis (Table 1) [23–29].”

What the sources say

• Not checked yetcites [23] Lamb BT, Call LM, Slunt HH, Bardel KA, Lawler AM, Eckman CB, et al. Altered metabolism of familial Alzheimer’s disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet. 1997;6:1535–41. source
• Not checked yetcites [24] Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997;19:939–45. source
• Not checked yetcites [25] Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373:523–7. source
• Not checked yetcites [26] Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA. 1997;94:13287–92. source
• Not checked yetcites [27] Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999;274:6483–92. source
• Not checked yetcites [28] Reaume AG, Howland DS, Trusko SP, Savage MJ, Lang DM, Greenberg BD, et al. Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer’s disease mutations and a “humanized” Abeta sequence. The. J Biol Chem. 1996;271:23380–8. source
• Not checked yetcites [29] Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000;20:4050–8. source

In the paper

“These findings, consistent with previous comparisons of protein and mRNA data [65], strongly support the utility of protein profiling in AD and its complementarity with transcriptomic studies.”

What the sources say

• Not checked yetcites [65] de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C. Global signatures of protein and mRNA expression levels. Mol Biosyst. 2009;5:1512–26.

In the paper

“As discussed in the next section, collaborative efforts, such as AMP-AD, and advances in high-throughput proteomics have allowed the field to overcome many of these challenges and identify a systems-based proteomic organization conserved across brain samples from a variety of different AD cohorts and cortical regions.”

In the paper

“Cell type-specific perturbations appear to drive many of these disease-associated network changes with glia-enriched modules most increased in AD and neuronal modules most decreased in disease (Fig. 1).”

In the paper

“Variants of the microglial TREM2 gene have been found to increase the risk of sporadic AD by approximately 3- to 5-fold [56, 57].”

What the sources say

• Not checked yetcites [56] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, et al. TREM2 variants in Alzheimer’s disease. N. Engl J Med. 2013;368:117–27. source
• Not checked yetcites [57] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl J Med. 2013;368:107–16. source

In the paper

“Alterations in these disease-associated modules are strongly conserved across cohorts and cortical regions, allowing for the recent construction of a large consensus AD brain network derived from hundreds of brain samples [96].”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“Cell populations display a wide dynamic range of protein concentrations driven by their immediate surroundings.”

In the paper

“Furthermore, as discussed below, the application of network approaches to protein interactomes has helped characterize key aggregation mechanisms underlying the biochemical phase of AD.”

In the paper

“Despite a variety of technological advancements, proteomic analysis of bulk human brain tissue has its limitations. Perhaps the biggest challenge is the inter- and intra-regional variability found throughout brain tissue.”

In the paper

“While the network proteomic analysis of bulk tissue can provide an invaluable view of global cell type-specific changes in disease, this approach is limited in examination of the cellular microenvironment and its effects on protein levels.”

In the paper

“The identification of modules altered in AsymAD also provides a window into the earliest drivers of AD and may help guide the mechanistic evaluation of preclinical disease.”

In the paper

“For example, genetic risk factor enrichment can identify those modules more likely to have causative, rather than reactive, roles in disease and support further investigations into the potential disease-related mechanisms associated with these protein communities.”

In the paper

“Therefore, DIA results in the identification of nearly all detectable peptides within a selected mass range, allowing for comprehensive and accurate quantification of identified proteins in the sample with minimal missing values [81, 82].”

What the sources say

• Not checked yetcites [81] Meyer JG, Schilling B. Clinical applications of quantitative proteomics using targeted and untargeted data-independent acquisition techniques. Expert Rev Proteom. 2017;14:419–29. source
• Not checked yetcites [82] Crowgey EL, Matlock A, Venkatraman V, Fert-Bober J, Van Eyk JE. Mapping biological networks from quantitative data-independent acquisition mass spectrometry: data to knowledge pipelines. Methods Mol Biol. 2017;1558:395–413. source

In the paper

“Using high-throughput MS techniques, these studies have revealed highly reproducible modules across the AD proteome, several of which consistently demonstrate strong correlations to AD diagnosis, Aβ burden, and other phenotypic traits of disease.”

In the paper

“Yet, these network studies have also yielded AD-associated modules with no apparent links to specific cell types, suggesting these protein changes reflect the biochemical phase of AD.”

In the paper

“The wealth of evidence indicating the causative role of these cellular processes in AD pathogenesis strongly supports a more holistic approach to AD investigation and biomarker discovery.”

In the paper

“Peroxiredoxin 1 (PRDX1), another hub of this module, is a family member of antioxidant enzymes also implicated in protective cellular responses [125].”

What the sources say

• Not checked yetcites [125] Ding C, Fan X, Wu G. Peroxiredoxin 1—an antioxidant enzyme in cancer. J Cell Mol Med. 2017;21:193–202. source

In the paper

“The authors subsequently concluded that RNA-binding proteins may drive the proteopathic “biochemical” phase of AD.”

What the sources say

• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

In the paper

“network proteomics has revealed one other highly conserved AD-associated module with possible links to this phase of disease. Unlike the RNA-binding/splicing modules, this module is consistently downregulated throughout AD and strongly associated with the cytoskeleton (Fig. 1) [62, 63, 96].”

What the sources say

• Not checked yetcites [62] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“This analysis successfully organized the U1-70K interactome into seven biologically meaningful modules, two of which demonstrated a strong association with pathogenic U1-70K domains.”

What the sources say

• Not checked yetcites [138] Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, et al. RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem. 2018;293:11047–66. source

In the paper

“These ribonucleoproteins, constituents of the spliceosome complex responsible for RNA processing, are mislocalized in AD to the cytoplasm of neuronal cell bodies where they aggregate with NFTs and contribute to widespread alterations in RNA processing [134].”

What the sources say

• Not checked yetcites [134] Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci USA. 2013;110:16562–7. source

In the paper

“This FACS pipeline can be easily optimized for proteomic analyses of multiple cell types with >95% purity by confidently excluding debris.”

In the paper

“BioID has been used extensively in vitro [162–166] to define interacting protein partners and proteins in subcellular compartments, but its application in vivo is limited.”

What the sources say

• Not checked yetcites [162] Chen AL, Kim EW, Toh JY, Vashisht AA, Rashoff AQ, Van C, et al. Novel components of the Toxoplasma inner membrane complex revealed by BioID. mBio. 2015;6:e02357–14.
• Not checked yetcites [163] Gupta GD, Coyaud E, Goncalves J, Mojarad BA, Liu Y, Wu Q, et al. A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell. 2015;163:1484–99. source
• Not checked yetcites [164] Morriswood B, Havlicek K, Demmel L, Yavuz S, Sealey-Cardona M, Vidilaseris K, et al. Novel bilobe components in Trypanosoma brucei identified using proximity-dependent biotinylation. Eukaryot Cell. 2013;12:356–67. source
• Not checked yetcites [165] Dingar D, Kalkat M, Chan PK, Srikumar T, Bailey SD, Tu WB, et al. BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors. J Proteom. 2015;118:95–111. source
• Not checked yetcites [166] Kehrer J, Frischknecht F, Mair GR. Proteomic analysis of the plasmodium berghei gametocyte egressome and vesicular bioID of osmiophilic body proteins identifies merozoite TRAP-like protein (MTRAP) as an essential factor for parasite transmission. Mol Cell Proteom. 2016;15:2852–62. source

In the paper

“Cell type-specific proteomics in the human brain is currently in its infancy, primarily due to the inability to isolate live, pure cell populations from frozen brain and limited access to fresh postmortem tissue.”

In the paper

“By fusing BirA* to a bait protein with a synaptic localization signal or nuclear pore signal, BirA* expression was specifically guided to the synapse or nuclear pore complex to achieve biotinylation of the respective proteomes [167, 168].”

What the sources say

• Not checked yetcites [167] Kim DI, Birendra KC, Zhu W, Motamedchaboki K, Doye V, Roux KJ. Probing nuclear pore complex architecture with proximity-dependent biotinylation. Proc Natl Acad Sci USA. 2014;111:E2453–61. source
• Not checked yetcites [168] Uezu A, Kanak DJ, Bradshaw TW, Soderblom EJ, Catavero CM, Burette AC, et al. Identification of an elaborate complex mediating postsynaptic inhibition. Science. 2016;353:1123–9. source

In the paper

“Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology.”

What the sources say

• Not checked yetcites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

In the paper

“One inherent limitation of MACS and FACS is that live neurons cannot be sampled from adult brain, tremendously limiting our ability to understand neuron-specific proteomic changes occurring in vivo, as described below.”

What the sources say

• Not checked yetcites Table 2

In the paper

“LCM-based MS results in a lower proteome coverage compared to bulk brain proteomics, and the inability to confidently exclude contamination by cells that are not of interest poses a challenge (Table 2).”

In the paper

“Proximity labeling with enzymes is another strategy to achieve cell type-specific global proteomic labeling [160].”

What the sources say

• Not checked yetcites [160] Chen CL, Perrimon N. Proximity-dependent labeling methods for proteomic profiling in living cells. Wiley Interdiscip Rev Dev Biol. 2017;6:10.1002/wdev.272.

In the paper

“Apoe protein was also detected within Aβ plaque-associated microglia, suggesting a role for Apoe in phagocytic clearance of Aβ.”

What the sources say

• Not checked yetcites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

In the paper

“This is reflected in the global AD network proteome, which consistently demonstrates the progressive downregulation of synaptic modules in asymptomatic and symptomatic AD brains, a finding that appears to be preserved across various cortical brain regions [62, 96, 105].”

What the sources say

• Not checked yetcites [62] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source
• Not checked yetcites [105] Higginbotham L, Dammer EB, Duong DM, Modeste E, Montine TJ, Lah JJ, et al. Network analysis of a membrane-enriched brain proteome across stages of Alzheimer’s disease. Proteomes. 2019;7:30. source

In the paper

“Emerging evidence in AD mouse models indicates this homeostatic, microglia-mediated synaptic phagocytosis may be one of the earliest events in AD progression and contribute to synaptic losses during asymptomatic stages of disease [143].”

What the sources say

• Not checked yetcites [143] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. source

In the paper

“A recent study compared the proteomic profiles of MACS-enriched microglia and FACS-isolated microglia from adult mouse brain and found that the FACS-isolated microglia proteome was significantly enriched in canonical microglial proteins (e.g., Ctsd) and contained much lower levels of non-microglia proteins (e.g., Gfap) [153].”

What the sources say

• Not checked yetcites [153] Rayaprolu S, Gao T, Xiao H, Ramesha S, Duong DM, Dammer EB, et al. Quantitative multiplexed proteomics of mouse microglia by flow-cytometric sorting reveals a core set of highly-abundant microglial proteins. bioRxiv. https://doi.org/10.1101/802694. source

In the paper

“The fidelity of in vivo BONCAT has thus far only been shown in mouse excitatory neurons”

In the paper

“These early CSF protein derangements suggest the aberrant exocytosis of neuronal components into the extracellular space, which could be explained by synaptic pruning.”

In the paper

“Of 4133 proteins identified, 187 microglial proteins were differentially expressed in 5xFAD mice, including proteins with known (e.g., Apoe) and novel (e.g., Cotl1) relevance to AD biology.”

What the sources say

• Not checked yetcites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

In the paper

“Both validation methods offer highly sensitive and accurate quantitation, though MS may offer certain advantages, such as highly selective target detection using unique peptides and the ability to cost-effectively analyze large panels of proteins in an initial verification phase prior to more expensive validation efforts.”

In the paper

“More recently, BioID was used to effectively label proteins within flies (Drosophila melanogaster) or worms (Caenorhabditis elegans) [169].”

What the sources say

• Not checked yetcites [169] Branon TC, Bosch JA, Sanchez AD, Udeshi ND, Svinkina T, Carr SA, et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. 2018;36:880–7. source

In the paper

“MS may offer certain advantages, such as highly selective target detection using unique peptides and the ability to cost-effectively analyze large panels of proteins in an initial verification phase prior to more expensive validation efforts.”

In the paper

“These high rates of overlapping pathologies combined with additional biological heterogeneity introduced by individual genetic and environmental factors make for an overwhelmingly complex pathophysiological landscape among the over 40 million individuals thought to be living with AD worldwide.”

In the paper

“These assays are capable of high-fidelity validation, versatile in application, and easier to execute than MS-based assays.”

What the sources say

• Not checked yetcites [182] Kim CH, Tworoger SS, Stampfer MJ, Dillon ST, Gu X, Sawyer SJ, et al. Stability and reproducibility of proteomic profiles measured with an aptamer-based platform. Sci Rep. 2018;8:8382.
• Not checked yetcites [183] Giudice V, Biancotto A, Wu Z, Cheung F, Candia J, Fantoni G, et al. Aptamer-based proteomics of serum and plasma in acquired aplastic anemia. Exp Hematol. 2018;68:38–50. source

In the paper

“Such a reductionist approach to AD stands to hinder advancements in diagnostic subtyping, disease monitoring, and therapeutic development.”

In the paper

“Plasma biomarker discovery represents another potential extension of AD brain network analysis.”

In the paper

“As discussed previously, the anti-inflammatory microglia-enriched MSN module is elevated in the AsymAD brain and thought to play a causative role in disease pathogenesis.”

In the paper

“Second, in the absence of high-quality, commercially available antibodies or aptamers, assays must be generated de novo, optimized, and validated separately, a process that can also be costly and time-consuming.”

In the paper

“A major advantage of APEX over BioID, is the rapid kinetics and high efficiency of labeling”

In the paper

“In two separate smaller analyses of AD CSF, many of the same AD-associated synaptic and metabolic biomarkers were identified, further supporting the reproducibility these systems-based CSF marker panels [78, 172].”

What the sources say

• Not checked yetcites [78] Bai B, Wang X, Li Y, Chen PC, Yu K, Dey KK, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer’s disease progression. Neuron 2020;105:975–91. source
• Not checked yetcites [172] Bader JM, Geyer PE, Muller JB, Strauss MT, Koch M, Leypoldt F, et al. Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer’s disease. Mol Syst Biol. 2020;16:e9356. source

In the paper

“TurboID retains the promiscuous biotinylation property of BioID, but rapidly labels proteins in 10 minutes compared to the 18–24 hours required by BioID (Fig. 2).”

In the paper

“These 15 brain modules were also high-yield sources of markers differentially expressed in AD CSF, collectively harboring nearly 300 proteins with significantly altered levels in AD spinal fluid compared to controls.”

What the sources say

• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

In the paper

“The direct proximity of CSF to the brain presents a strong rationale for discovery-driven integration of these two proteomes.”

In the paper

“Interestingly, the final CSF marker panels demonstrated AD-specificity and altered levels in AsymAD spinal fluid, indicating a potential role for these panels in preclinical disease stages.”

What the sources say

• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

In the paper

“however, APEX is not suitable for in vivo studies due to the toxicity of biotin-phenol.”

In the paper

“First, the costs of commercially available antibody or aptamer reagents necessary for large-scale studies of hundreds or thousands of proteins in sizeable clinical research studies can be prohibitive, limiting validation and translation efforts.”

In the paper

“TurboID-based proteome labeling has been successfully applied in flies and worms without much toxicity and with high labeling efficiency [169].”

What the sources say

• Not checked yetcites [169] Branon TC, Bosch JA, Sanchez AD, Udeshi ND, Svinkina T, Carr SA, et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. 2018;36:880–7. source

In the paper

“SMOC1, YWHAZ, ALDOA, and MAP1B emerged as biomarkers that could best discriminate between individuals with AD and non-AD cognitive impairment, correlating well with Aβ and tau levels [192].”

What the sources say

• Not checked yetcites [192] Zhou M, Haque RU, Dammer EB, Duong DM, Ping L, Johnson ECB, et al. Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer’s disease. Clin Proteom. 2020;17:19. source

In the paper

“As Cilento et al. argue in a recent review of targeted MS in AD biomarker discovery, these approaches provide a cost-effective means of systematically verifying large panels of protein biomarker candidates prior to more expensive and large-scale validation testing [187].”

What the sources say

• Not checked yetcites [187] Cilento EM, Jin L, Stewart T, Shi M, Sheng L, Zhang J. Mass spectrometry: a platform for biomarker discovery and validation for Alzheimer’s and Parkinson’s diseases. J Neurochem. 2019;151:397–416. source

In the paper

“Several proteins, including tau and neurofilaments, were significantly increased in AD CSF and capable of distinguishing AD cases from controls and non-AD dementia.”

What the sources say

• Not checked yetcites [192] Zhou M, Haque RU, Dammer EB, Duong DM, Ping L, Johnson ECB, et al. Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer’s disease. Clin Proteom. 2020;17:19. source

In the paper

“Targeted MS approaches have been increasingly employed for the detection and quantification of protein biomarkers from biofluids [187].”

What the sources say

• Not checked yetcites [187] Cilento EM, Jin L, Stewart T, Shi M, Sheng L, Zhang J. Mass spectrometry: a platform for biomarker discovery and validation for Alzheimer’s and Parkinson’s diseases. J Neurochem. 2019;151:397–416. source