Synaptic Proteome Remodeling in the Angular Gyrus Identifies Molecular Signatures of Cognitive Decline and Resilience in Alzheimer’s Disease
Keywords:
Alzheimer’s Disease, Synaptic Proteomics, Angular Gyrus, Cognitive Resilience, Tandem Mass Tag, Neurodegeneration, LC-MS3Abstract
Synaptic degeneration is a hallmark of early Alzheimer’s disease (AD) and is closely linked to cognitive impairment. The angular gyrus, a key cognitive hub, is particularly vulnerable to AD pathology. This study aimed to characterize synaptic proteomic alterations in the angular gyrus across individuals with varying cognitive outcomes and AD pathology. We analyzed synaptic fractions from post-mortem angular gyrus tissue of 100 individuals divided into four diagnostic groups (Normal, Dementia-AD, Resilient, Frail). Synaptic proteins were isolated using Syn-PER, followed by Tandem Mass Tag (TMT)-based LC-MS3 proteomic analysis. A total of 3,924 high-confidence synaptic proteins were quantified, and group-wise comparisons were performed using FDR-corrected statistical analyses. A total of 123 synaptic proteins were differentially expressed across diagnostic groups. Compared to the Normal group, the Dementia-AD group exhibited significant downregulation of key synaptic proteins (e.g., SNAP25, PSD-95) and upregulation of immune-related markers (e.g., TREM2, CD68). Resilient individuals preserved the expression of core synaptic proteins despite high AD pathology, suggesting molecular mechanisms of cognitive protection. Gene Ontology analysis revealed enrichment in pathways related to synaptic signaling, vesicle trafficking, and immune activation. These findings support a model in which cognitive decline results from both synaptic loss and neuroinflammatory processes. This study provides a comprehensive proteomic map of synaptic alterations in the angular gyrus and reveals molecular signatures associated with both cognitive decline and resilience in AD. These insights highlight potential biomarkers and therapeutic targets aimed at preserving synaptic function and delaying cognitive deterioration.
References
Bilousova, T., Miller, C. A., Poon, W. W., Vinters, H. V, Corrada, M. M., Kawas, C. H., Hayden, E. Y., Teplow, D. B., Glabe, C., Albay, R., Cole, G. M., Teng, E., & Gylys, K. H. (2017). Synaptic Amyloid-Β Oligomers Precede P-Tau and Differentiate High Pathology Control Cases. American Journal of Pathology, 186(1), 185–198. https://doi.org/10.1016/j.ajpath.2015.09.018
Carlos, A. J., Tong, L., Prieto, G. A., & Cotman, C. W. (2017). IL-1β Impairs Retrograde Flow of BDNF Signaling by Attenuating Endosome Trafficking. Journal of Neuroinflammation, 14(1). https://doi.org/10.1186/s12974-017-0803-z
Carlyle, B. C., Kandigian, S. E., Kreuzer, J., Das, S., Trombetta, B. A., Kuo, Y., Bennett, D. A., Schneider, J. A., Petyuk, V., Kitchen, R. R., Morris, R., Nairn, A. C., Hyman, B. T., Haas, W., & Arnold, S. E. (2021). Synaptic Proteins Associated With Cognitive Performance and Neuropathology in Older Humans Revealed by Multiplexed Fractionated Proteomics. Neurobiology of Aging, 105, 99–114. https://doi.org/10.1016/j.neurobiolaging.2021.04.012
Carlyle, B. C., Kandigian, S. E., Kreuzer, J., Das, S., Trombetta, B. A., Kuo, Y., Bennett, D. A., Schneider, J. A., Petyuk, V., Kitchen, R. R., Morris, R. T., Nairn, A. C., Hyman, B. T., Haas, W., & Arnold, S. E. (2020). Multiplexed Fractionated Proteomics Reveals Synaptic Factors Associated With Cognitive Resilience in Alzheimer’s Disease. https://doi.org/10.1101/2020.07.31.230680
Colom‐Cadena, M., Spires‐Jones, T. L., Zetterberg, H., Blennow, K., Caggiano, A., DeKosky, S. T., Fillit, H., Harrison, J., Schneider, L. S., Scheltens, P., Haan, W. d, Grundman, M., Dyck, C. H. v, Izzo, N. J., & Catalano, S. M. (2020). The Clinical Promise of Biomarkers of Synapse Damage or Loss in Alzheimer’s Disease. Alzheimer S Research & Therapy, 12(1). https://doi.org/10.1186/s13195-020-00588-4
Coomans, E. M., Schoonhoven, D. N., Tuncel, H., Verfaillie, S. C., Wolters, E. E., Boellaard, R., Ossenkoppele, R., Braber, A. d, Scheper, W., Schober, P., Sweeney, S., Ryan, J. M., Schuit, R. C., Windhorst, A. D., Barkhof, F., Scheltens, P., Golla, S. S., Hillebrand, A., Gouw, A. A., & Berckel, B. N. v. (2021). In Vivo Tau Pathology Is Associated With Synaptic Loss and Altered Synaptic Function. Alzheimer S Research & Therapy, 13(1). https://doi.org/10.1186/s13195-021-00772-0
Dando, O., McGeachan, R. I., McQueen, J., Baxter, P., Rockley, N., McAlister, H., Prasad, A., He, X., King, D., Rose, J., Jones, P., Tulloch, J., Chandran, S., Smith, C., Hardingham, G. E., & Spires‐Jones, T. L. (2024). Synaptic Gene Expression Changes in Frontotemporal Dementia Due to TheMAPT10+16 Mutation. https://doi.org/10.1101/2024.04.09.24305501
Deng, Y., Wei, J., Cheng, J., Zhong, P., Zhe, X., Liu, A., Lin, L., Chen, S., & Yan, Z. (2016). Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer’s Disease. Journal of Alzheimer S Disease, 53(4), 1419–1432. https://doi.org/10.3233/jad-160167
Dey, K., Wang, H., Niu, M., Bai, B., Wang, X., Li, Y., Cho, J.-H., Tan, H., Mishra, A., High, A. A., Chen, P., Wu, Z., Beach, T. G., & Peng, J. (2019). Deep Undepleted Human Serum Proteome Profiling Toward Biomarker Discovery for Alzheimer’s Disease. Clinical Proteomics, 16(1). https://doi.org/10.1186/s12014-019-9237-1
Gajera, C. R., Fernandez, R., Postupna, N., Montine, K. S., Fox, E., Tebaykin, D., Angelo, M., Bendall, S. C., Keene, C. D., & Montine, T. J. (2019). Mass Synaptometry: High-Dimensional Multi Parametric Assay for Single Synapses. Journal of Neuroscience Methods, 312, 73–83. https://doi.org/10.1016/j.jneumeth.2018.11.008
Haytural, H., Mermelekas, G., Emre, C., Nigam, S. M., Carroll, S. L., Winblad, B., Bogdanović, N., Barthet, G., Granholm, A., Orre, L. M., Tjernberg, L. O., & Frykman, S. (2020). The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease. Molecular & Cellular Proteomics, 19(1), 128–141. https://doi.org/10.1074/mcp.ra119.001737
Hesse, R., Hurtado, M. L., Jackson, R. J., Eaton, S. L., Herrmann, A. G., Colom‐Cadena, M., Tzioras, M., King, D., Rose, J., Tulloch, J., McKenzie, C.-A., Smith, C., Henstridge, C. M., Lamont, D. J., Wishart, T. M., & Spires‐Jones, T. L. (2019). Comparative Profiling of the Synaptic Proteome From Alzheimer’s Disease Patients With Focus on the APOE Genotype. Acta Neuropathologica Communications, 7(1). https://doi.org/10.1186/s40478-019-0847-7
Huang, M., Darvas, M., Keene, C. D., & Wang, Y. (2019). Targeted Quantitative Proteomic Approach for High-Throughput Quantitative Profiling of Small GTPases in Brain Tissues of Alzheimer’s Disease Patients. Analytical Chemistry, 91(19), 12307–12314. https://doi.org/10.1021/acs.analchem.9b02485
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., Thambisetty, M., Montine, T. J., Lee, E. B., Trojanowski, J. Q., Beach, T. G., Reiman, E. M., Haroutunian, V., Wang, M., Schadt, E. E., & Seyfried, N. T. (2020). Large-Scale Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated With Microglia and Astrocyte Activation. Nature Medicine, 26(5), 769–780. https://doi.org/10.1038/s41591-020-0815-6
Ke, C., Shan, S., Tan, Y., Cao, Y., Xie, zhengrong, Pan, J., & Zhang, W. (2023). TMT-based Quantitative Proteomics Reveals That Electroacupuncture Has Neuroprotective Effect on Alzheimer’s Disease Rats Through Synaptic Vesicle Cycle And glutamatergic synapse signal Pathways. https://doi.org/10.21203/rs.3.rs-2932401/v1
King, D., Holt, K., Toombs, J., He, X., Dando, O., Okely, J. A., Tzioras, M., Rose, J., Gunn, C., Correia, A., Montero, C., McAlister, H., Tulloch, J., Lamont, D. J., Taylor, A. M., Harris, S. E., Redmond, P., Cox, S. R., Henstridge, C. M., & Spires‐Jones, T. L. (2022). Synaptic Resilience Is Associated With Maintained Cognition During Ageing. Alzheimer S & Dementia, 19(6), 2560–2574. https://doi.org/10.1002/alz.12894
Krivinko, J. M., Erickson, S., Ding, Y., Sun, Z., Penzes, P., MacDonald, M. L., Yates, N. A., Ikonomović, M. D., López, O. L., Sweet, R. A., & Kofler, J. (2018). Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer’s Disease. American Journal of Psychiatry, 175(10), 999–1009. https://doi.org/10.1176/appi.ajp.2018.17080858
Kurbatskaya, K., Phillips, E. C., Croft, C. L., Dentoni, G., Hughes, M. M., Wade, M., Al‐Sarraj, S., Troakes, C., O’Neill, M. J., Perez‐Nievas, B. G., Hanger, D. P., & Noble, W. (2016). Upregulation of Calpain Activity Precedes Tau Phosphorylation and Loss of Synaptic Proteins in Alzheimer’s Disease Brain. Acta Neuropathologica Communications, 4(1). https://doi.org/10.1186/s40478-016-0299-2
Mecca, A. P., O’Dell, R. S., Sharp, E., Banks, E., Bartlett, H. H., Zhao, W., Lipior, S., Diepenbrock, N. G., Chen, M., Naganawa, M., Toyonaga, T., Nabulsi, N., Wyk, B. C. V, Arnsten, A. F., Huang, Y., Carson, R. E., & Dyck, C. H. v. (2022). Synaptic Density and Cognitive Performance in Alzheimer’s Disease: A PET Imaging Study With [11C]UCB‐J. Alzheimer S & Dementia, 18(12), 2527–2536. https://doi.org/10.1002/alz.12582
Miyamoto, M., Kuzuya, A., Noda, Y., Ueda, S., Asada‐Utsugi, M., Ito, S., Fukusumi, Y., Kawachi, H., Takahashi, R., & Kinoshita, A. (2020). Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1. Journal of Alzheimer S Disease, 75(1), 173–185. https://doi.org/10.3233/jad-200071
Paulo, J. A., & Schweppe, D. K. (2021). Advances in Quantitative High‐throughput Phosphoproteomics With Sample Multiplexing. Proteomics, 21(9). https://doi.org/10.1002/pmic.202000140
Prinkey, K., Thompson, E. J., Saikia, J. M., Cid, T., & Doré, K. (2024). Fluorescence Lifetime Imaging of AMPA Receptor Endocytosis in Living Neurons: Effects of Aβ and PP1. Frontiers in Molecular Neuroscience, 17. https://doi.org/10.3389/fnmol.2024.1409401
Russell, C., Heslegrave, A., Mitra, V., Zetterberg, H., Pocock, J. M., Ward, M., & Pike, I. (2016). Combined Tissue and Fluid Proteomics With Tandem Mass Tags to Identify Low‐abundance Protein Biomarkers of Disease in Peripheral Body Fluid: An Alzheimer’s Disease Case Study. Rapid Communications in Mass Spectrometry, 31(2), 153–159. https://doi.org/10.1002/rcm.7777
Scaduto, P., Lauterborn, J. C., Cox, C. D., Fracassi, A., Zeppillo, T., Gutierrez, B. A., Keene, C. D., Crane, P. K., Mukherjee, S., Russell, W. K., Taglialatela, G., & Limón, A. (2022). Functional Excitatory to Inhibitory Synaptic Imbalance and Loss of Cognitive Performance in People With Alzheimer’s Disease Neuropathologic Change. Acta Neuropathologica, 145(3), 303–324. https://doi.org/10.1007/s00401-022-02526-0
Singh, N. K., Golime, R., Acharya, J., & Palit, M. (2020). Quantitative Proteomic Changes After Organophosphorous Nerve Agent Exposure in the Rat Hippocampus. Acs Chemical Neuroscience, 11(17), 2638–2648. https://doi.org/10.1021/acschemneuro.0c00311
Storey, A. J., Hardman, R. E., Byrum, S. D., Mackintosh, S. G., Edmondson, R. D., Wahls, W. P., Tackett, A. J., & Lewis, J. A. (2020). Accurate and Sensitive Quantitation of the Dynamic Heat Shock Proteome Using Tandem Mass Tags. Journal of Proteome Research, 19(3), 1183–1195. https://doi.org/10.1021/acs.jproteome.9b00704
Woody, S. K., Zhou, H., Ibrahimi, S., Dong, Y., & Zhao, L. (2016). Human ApoE Ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on v-Type H+-ATPase. Journal of Alzheimer S Disease, 53(3), 1015–1031. https://doi.org/10.3233/jad-160307
Zhuang, L., Li, C., Peng, F., Xue, E., Li, W., Sun, X., Chen, P., Zhou, Q., & Xue, L. (2023). Depletion of ESCRT Ameliorates APP‐induced AD‐like Symptoms in Drosophila. Journal of Cellular Physiology, 238(7), 1567–1579. https://doi.org/10.1002/jcp.31035
