Proteomic analysis of neurons microdissected from formalin-fixed, paraffin-embedded Alzheimer’s disease brain tissue
Open accessAbstract
The vast majority of human tissue specimens are formalin-fixed, paraffin embedded (FFPE) archival samples, making this type of tissue a potential gold mine for medical research. It is now accepted that proteomics can be done using FFPE tissue and can generate similar results as snap-frozen tissue. However, the current methodology requires a large amount of starting protein, limiting the questions that can be answered in these types of proteomics studies and making cell-type specific proteomics studies difficult. Cell-type specific proteomics has the potential to greatly enhance understanding of cell functioning in both normal and disease states. Therefore, here we describe a new method that allows localized proteomics on individual cell populations isolated from FFPE tissue sections using laser capture microdissection. To demonstrate this technique we microdissected neurons from archived tissue blocks of the temporal cortex from patients with Alzheimer’s disease. Using this method we identified over 400 proteins in microdissected neurons; on average 78% that were neuronal and 50% that were associated with Alzheimer’s disease. Therefore, this technique is able to provide accurate and meaningful data and has great potential for any future study that wishes to perform localized proteomics using very small amounts of archived FFPE tissue.
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LCM has been used to micro-dissect neurons from both fresh frozen human brain and formalin-fixed paraffin embedded tissue sections for proteomic analyses.
“LCM has been used to micro-dissect neurons from both fresh frozen human brain and formalin-fixed paraffin embedded tissue sections for proteomic analyses [144, 145].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [144]
Drummond et al. found proteins increased in rapidly progressive AD plaques (e.g., α-synuclein) to be decreased or have no known involvement in sporadic AD.
“LCM coupled to LFQ-MS of these samples revealed proteins increased in rapidly progressive AD plaques (e.g., α-synuclein) to be decreased or have no known involvement in sporadic AD [144].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [144]
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“LCM has been successfully applied to isolate tumor cells [17], neurons affected by Parkinson [18] or Alzheimer disease [19], virus-infected cells [20], organelles [21], and GCs [22].”
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“isolated neuronal cells from temporal cortex FFPE samples with severe Alzheimer’s using the LCM-LC-MS/MS technique and identified more than 400 proteins of which 78% were of neuronal origin and about 200 proteins were associated with Alzheimer’s disease [29].”
MethodGomez‐Gómez, À., Sabbaghi, M., Haro, N., Albanell, J., Menéndez, S., Gonzàlez‐Farré, M., Gil‐Gómez, G., Rovira, A., & Pozo, Ó. J. (2020) · Talanta · doi:10.1016/j.talanta.2020.121740 · Cited by 17 · see citing works
Simão, D. F., Gomes, C. M., Alves, P. M., & Brito, C. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107883 · Cited by 14 · see citing works
Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood
Leitner, D., William, C. M., Faustin, A., Askenazi, M., Kanshin, E., Snuderl, M., McGuone, D., Wısnıewskı, T., Ueberheide, B. M., Gould, L., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02414-7 · Cited by 14 · see citing works
Self-citationRadford, R. A. W., Rayner, S. L., Szwaja, P., Morsch, M., Cheng, F., Zhu, T., Widagdo, J., Anggono, V., Pountney, D. L., Chung, R. S., et al. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15796 · Cited by 12 · see citing works
“Alternate techniques such as immunohistochemistry (IHC), biotinylation (Prikas et al., 2022), and proximity- ligation detection methods provide precise in situ labeling of individual protein components but are limited by antibody combination limits (Duraiyan et al., 2012; Söderberg et al., 2008).”
The use of localized proteomics to identify the drivers of Alzheimer's disease pathogenesis
Drummond, E., & Wısnıewskı, T. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.208570 · Cited by 13 · see citing works
“…this challenge we developed our localized proteomics technique, which combines laser capture microdissection (LCM) and label-free quantitative LC-MS to simultaneously quantify expression of hundreds of proteins in an unbiased manner using microscopic amounts of tissue (Drummond et al., 2015).”
MethodSelf-citationRecent advances in applying mass spectrometry and systems biology to determine brain dynamics
Scifo, E., Calza, G., Fuhrmann, M., Soliymani, R., Baumann, M., & Lalowski, M. M. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2017.1335200 · Cited by 13 · see citing works
“Analysis of temporal cortex neurons from FFPE AD human samples [110] identified 78% neuronal proteins of which 50% were associated with AD.”
BackgroundUsing Proteomics to Understand Alzheimer’s Disease Pathogenesis
Drummond, E., & Wısnıewskı, T. (2019) · Codon Publications eBooks · doi:10.15586/alzheimersdisease.2019.ch3 · Cited by 12 · see citing works
Self-citationRobust collection and processing for label-free single voxel proteomics
Kitata, R. B., Veličković, M., Xu, Z., Zhao, R., Scholten, D., Chu, R., Orton, D., Chrisler, W., Zhang, T., Mathews, J. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-54643-x · Cited by 15 · see citing works
“Drummond et al. developed a wet cap-assisted localized proteomics method for quantitative cell type-speci fi c proteomics in Alz-heimer ’ s disease (AD) research 28,29 .”
InfluentialSun, K. T., & Mok, S. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00512 · Cited by 10 · see citing works
“Many proteins have been found to associate with the soluble and aggregated forms of tau and A β [183].”
Drummond, E., Nayak, S., Ueberheide, B. M., & Wısnıewskı, T. (2017) · Neuromethods · doi:10.1007/978-1-4939-7119-0_18 · Cited by 10 · see citing works
Self-citationGordon, A., & Gousset, K. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1178-4_3 · Cited by 9 · see citing works
Alldred, M. J., Ibrahim, K. W., Pidikiti, H., Chiosis, G., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01891-z · Cited by 7 · see citing works
“Previous studies indicate RNA-seq results are replicated by RT-qPCR and protein analysis [5, 7–9, 31, 36], but these data are derived from lamina specific neuronal samples.”
Iacono, D., Geraci-Erck, M., Peng, H., & Bouffard, J. (2016) · Journal of Visualized Experiments · doi:10.3791/54602 · Cited by 8 · see citing works
Soloperto, A., Palazzolo, G., Tsushima, H., Chieregatti, E., Vassalli, M., & Difato, F. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00101 · Cited by 6 · see citing works
“Finally, laser scissors can be applied to precisely isolate cells within cultures, or subpopulation of cells from brain tissues to apply targeted proteomic studies (Drummond et al., 2015), to remove pathological tissues, e.g., brain tumors, or alleviate epileptic seizures (Medvid et al., 2015).”
BackgroundUpdates on the study of lysosomal protein dynamics: possibilities for the clinic
Arora, D., Hackenberg, Y., Li, J., & Winter, D. (2023) · Expert Review of Proteomics · doi:10.1080/14789450.2023.2190515 · Cited by 5 · see citing works
Fixation Protocols for Neurohistology: Neurons to Genes
Mufson, E. J., Perez, S. E., Kelley, C. M., Alldred, M. J., & Ginsberg, S. D. (2020) · Neuromethods · doi:10.1007/978-1-0716-0428-1_2 · Cited by 4 · see citing works
Using Laser Capture Microdissection to Isolate Cortical Laminae in Nonhuman Primate Brain
Corgiat, B. A., & Mueller, C. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6990-6_8 · Cited by 4 · see citing works
Compilation of all known protein changes in the human Alzheimer’s disease brainPreprint
Askenazi, M., Kavanagh, T., Pires, G., Ueberheide, B. M., Wısnıewskı, T., & Drummond, E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.13.536828 · Cited by 4 · see citing works
Self-citationLes applications de la microdissection laser en histologie
Legrès, L. (2019) · médecine/sciences · doi:10.1051/medsci/2019166 · Cited by 3 · see citing works
Subcellular proteomics insights into Alzheimer's disease development
Liang, Z., Zhuang, H., Cao, X., Ma, G., & Shen, L. (2023) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.202200112 · Cited by 3 · see citing works
Jaramillo, C. J., Nedderman, D. M., Ahat, E., McElwee, J. L., Soper, M. D., Ballard, D. W., Zhang, L., Credille, K. M., Heady, G., Hsi, E. D., et al. (2025) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlaf108 · Cited by 2 · see citing works
Validation of a Mass Spectrometry–Based Proteomics Molecular Pathology Assay
Chapman, J. R., Baik, J., Mereuta, O. M., et al. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101487 · Cited by 2 · see citing works
“FFPE tissue is extremely stable and is stored at room temperature for decades with integrity (18).”
Metals and Mitochondria in Neurodegeneration
Plascencia‐Villa, G., José–Yacamán, M., & Perry, G. L. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804562-6.00015-4 · Cited by 2 · see citing works
Clinical proteomics of enervated neurons
Sengupta, M. B., Chakrabarti, A., Saha, S. G., & Mukhopadhyay, D. (2016) · Clinical Proteomics · doi:10.1186/s12014-016-9112-2 · Cited by 2 · see citing works
“A recent study with micro dissected neurons from the temporal cortex of AD brain has identified more than 400 proteins using LC–MS analysis [25].”
BackgroundProteomic Biomarkers in Alzheimer's disease
Cacabelos, R. (2016) · Diagnostic Pathology Open Access · doi:10.4172/2476-2024.1000103 · Cited by 2 · see citing works
“Novel techniques have been developed for proteomic bioanalysis of microdissected cells; 400 proteins have been identified in microdissected neurons, 50% of which were associated with AD [21].”
BackgroundSystems Biology: Methods and Applications
Titz, B., Knorr, A., Sewer, A., Martin, F. P., Ivanov, N. V., Talikka, M., Suarez, I. G., Peitsch, M. C., & Hoeng, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.12333-9 · Cited by 2 · see citing works
Probing Glioblastoma Tissue Heterogeneity with Laser Capture Microdissection
Gagner, J., & Zagzag, D. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7659-1_17 · Cited by 2 · see citing works
Morimoto, Y., Go, K., Suzuki, K., et al. (2026) · Hepatology Research · doi:10.1111/hepr.70133 · Cited by 1 · see citing works
“Liver tissues were collected from 1.5 mm 2 areas ( n = 6 per group), following established protocols [14–16].”
InfluentialInfrared Laser Ablation and Capture of Formalin-Fixed Paraffin-Embedded Tissue
Egbejiogu, B. C., Donnarumma, F., & Murray, K. K. (2024) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.4c00299 · Cited by 1 · see citing works
Making brain proteomics true to type
Wilson, R. S., & Nairn, A. C. (2018) · Nature Biotechnology · doi:10.1038/nbt.4077
Leitner, D., Mills, J. D., Pires, G., Faustin, A., Drummond, E., Kanshin, E., Nayak, S., Askenazi, M., Verducci, C., Chen, B. J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.27.223446
Self-citationDeciphering cell-type specific signal transduction in the brain: Challenges and promises
Roussarie, J.-P., & Rodriguez‐Rodriguez, P. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.09.009
Multi-omic analysis of the aging mouse brain
Kluever, V. (2021) · doi:10.53846/goediss-9022
Reyes, I., Kanshin, E., Tian, C., Faustin, A., Ueberheide, B. M., & Masurkar, A. V. (2024) · medRxiv · doi:10.1101/2024.08.27.24312663
Self-citationApplications of Nanotechnology in Degenerative Disorders of the Brain
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Nwosu, A. J., Chen, L., Kumar, R., Kwon, Y., Goodyear, S. M., Kardosh, A., Fulcher, J. M., & Pasa-Tolic, L. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.06.704439
The Use of Localized Proteomics to Understand the Pathogenesis of Alzheimer's Disease
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- Authors
- Drummond, E. S., Nayak, S., Ueberheide, B., & Wisniewski, T.
- Affiliations
- NYU Langone Health (US)
- Venue
- Scientific Reports
- Published
- 2015-10-21
- Volume
- 5
- Issue
- 1
- Pages
- 15456-15456
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4614382
- OpenAlex
- W2413556564
- Semantic Scholar
- c5ce84d3580953e996782c33c5b0a9a0b20a680b
- Cited by
- 78
- References
- 45
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 12 · 2016: 7
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG20245, AG08051)
- National Institute on Aging (AG20245, P30AG008051, AG 08051, R01AG020245)
- National Cancer Institute (P30CA016087)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced Biosensing Techniques and Applications
- Keywords
- Alzheimer's disease, formalin-fixed paraffin-embedded tissue, laser capture microdissection, neuronal proteome, temporal cortex, archival tissue, protein identification
- MeSH terms
- Alzheimer Disease, Brain, Gene Expression Regulation, Humans, Neurons, Protein Biosynthesis, Paraffin Embedding, Proteomics
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