Neurodegenerative diseases (NDDs) are associated with the accumulation of a range of misfolded proteins across the central nervous system and related autoimmune responses, including the generation of antibodies and the activation of immune cells. Both innate and adaptive immunity become mobilized, leading to cellular and humoral effects. The role of humoral immunity in disease onset and progression remains to be elucidated with rising evidence suggestive of positive (protection, repair) and negative (injury, toxicity) outcomes. In this study, we review advances in research of neuron-targeting autoantibodies in the most prevalent NDDs. We discuss their biological origin, molecular diversity and changes in the course of diseases, consider their relevance to the initiation and progression of pathology as well as diagnostic and prognostic significance. It is suggested that the emerging autoimmune aspects of NDDs not only could facilitate the early detection but also might help to elucidate previously unknown facets of pathobiology with relevance to the development of precision medicine.

Experimental Neurobiology Program National Institute of Mental Health Klecany Czech Republic

Faculty of Science and Engineering University of Greenwich London Chatham Maritime Kent ME4 4TB United Kingdom

Zobrazit více v PubMed

Hou YJ, Dan XL, Babbar M, Wei Y, Hasselbalch SG, Croteau DL. et al. Ageing as a risk factor for neurodegenerative disease. Nature Reviews Neurology. 2019;15:565–81. PubMed

Feigin VL, Nichols E, Alam T, Bannick MS, Beghi E, Blake N. et al. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:459–80. PubMed PMC

Focus on neurodegenerative disease. Nat Neurosci. 2018; 21: 1293. PubMed

Goedert M, Jakes R, Spillantini MG. The Synucleinopathies: Twenty Years On. J Parkinsons Dis. 2017;7:S51–S69. PubMed PMC

Koikkalainen J, Rhodius-Meester H, Tolonen A, Barkhof F, Tijms B, Lemstra AW. et al. Differential diagnosis of neurodegenerative diseases using structural MRI data. Neuroimage Clin. 2016;11:435–49. PubMed PMC

Marsh AP. Molecular mechanisms of proteinopathies across neurodegenerative disease: a review. Neurol Res Pract. 2019;1:35. PubMed PMC

Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron. 2011;71:35–48. PubMed

Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 2017;36:1474–92. PubMed PMC

Ovsepian SV, O'Leary VB, Zaborszky L, Ntziachristos V, Dolly JO. Synaptic vesicle cycle and amyloid beta: Biting the hand that feeds. Alzheimers Dement. 2018;14:502–13. PubMed

Ovsepian SV, O'Leary VB, Zaborszky L, Ntziachristos V, Dolly JO. Amyloid Plaques of Alzheimer's Disease as Hotspots of Glutamatergic Activity. Neuroscientist. 2019;25:288–97. PubMed PMC

Wishart TM, Parson SH, Gillingwater TH. Synaptic vulnerability in neurodegenerative disease. J Neuropathol Exp Neurol. 2006;65:733–9. PubMed

Henstridge CM, Pickett E, Spires-Jones TL. Synaptic pathology: A shared mechanism in neurological disease. Ageing Res Rev. 2016;28:72–84. PubMed

Alzheimer's Association Calcium Hypothesis W. Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement. 2017;13:178–82. e17. PubMed

Cummings J. The Role of Biomarkers in Alzheimer's Disease Drug Development. Adv Exp Med Biol. 2019;1118:29–61. PubMed PMC

Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Gotz J. Amyloid-beta and tau complexity - towards improved biomarkers and targeted therapies. Nat Rev Neurol. 2018;14:22–39. PubMed

Simren J, Ashton NJ, Blennow K, Zetterberg H. An update on fluid biomarkers for neurodegenerative diseases: recent success and challenges ahead. Curr Opin Neurobiol. 2020;61:29–39. PubMed

Zetterberg H, Burnham SC. Blood-based molecular biomarkers for Alzheimer's disease. Mol Brain. 2019;12:26. PubMed PMC

Zetterberg H, Schott JM. Biomarkers for Alzheimer's disease beyond amyloid and tau. Nat Med. 2019;25:201–3. PubMed

O'Bryant SE, Mielke MM, Rissman RA, Lista S, Vanderstichele H, Zetterberg H. et al. Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement. 2017;13:45–58. PubMed PMC

Ehrenberg AJ, Khatun A, Coomans E, Betts MJ, Capraro F, Thijssen EH. et al. Relevance of biomarkers across different neurodegenerative diseases. Alzheimers Res Ther. 2020;12:56. PubMed PMC

Hampel H, O'Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S. et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14:639–52. PubMed PMC

Pruss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021;21:798–813. PubMed PMC

Obrocki P, Khatun A, Ness D, Senkevich K, Hanrieder J, Capraro F. et al. Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course-a joint PhD student course at University College London and University of Gothenburg. Alzheimers Res Ther. 2020;12:20. PubMed PMC

DeMarshall CA, Han M, Nagele EP, Sarkar A, Acharya NK, Godsey G. et al. Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson's disease. Immunol Lett. 2015;168:80–8. PubMed

Nagele E, Han M, DeMarshall C, Belinka B, Nagele R. Diagnosis of Alzheimer's Disease Based on Disease-Specific Autoantibody Profiles in Human Sera. PLoS One. 2011;6:e23112. PubMed PMC

Nagele EP, Han M, Acharya NK, DeMarshall C, Kosciuk MC, Nagele RG. Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease. PLoS One. 2013;8:e60726. PubMed PMC

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L. et al. Identification of Candidate IgG Antibody Biomarkers for Alzheimer's Disease Through Screening of Synthetic Combinatorial Libraries. Cell. 2011;144:132–42. PubMed PMC

Hoffman W, Lakkis FG, Chalasani G. B Cells, Antibodies, and More. Clin J Am Soc Nephrol. 2016;11:137–54. PubMed PMC

Neiman M, Hellström C, Just D, Mattsson C, Fagerberg L, Schuppe-Koistinen I. et al. Individual and stable autoantibody repertoires in healthy individuals. Autoimmunity. 2019;52:1–11. PubMed

Jain RW, Yong VW. B cells in central nervous system disease: diversity, locations and pathophysiology. Nat Rev Immunol. 2021. PubMed PMC

Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol. 1995;7:812–8. PubMed

Hardy RR, Hayakawa K. Development of B cells producing natural autoantibodies to thymocytes and senescent erythrocytes. Springer Semin Immunopathol. 2005;26:363–75. PubMed

Madi A, Hecht I, Bransburg-Zabary S, Merbl Y, Pick A, Zucker-Toledano M. et al. Organization of the autoantibody repertoire in healthy newborns and adults revealed by system level informatics of antigen microarray data. Proc Natl Acad Sci U S A. 2009;106:14484–9. PubMed PMC

Mouthon L, Haury M, Lacroix-Desmazes S, Barreau C, Coutinho A, Kazatchkine MD. Analysis of the normal human IgG antibody repertoire. Evidence that IgG autoantibodies of healthy adults recognize a limited and conserved set of protein antigens in homologous tissues. J Immunol. 1995;154:5769–78. PubMed

Zhou ZH, Notkins AL. Polyreactive antigen-binding B (PAB+) cells are widely distributed and the PAB+ population consists of both B-1+ and B-1- phenotypes. Clin Exp Immunol. 2004;137:88–100. PubMed PMC

Sigounas G, Kolaitis N, Monell-Torrens E, Notkins AL. Polyreactive IgM antibodies in the circulation are masked by antigen binding. J Clin Immunol. 1994;14:375–81. PubMed

Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol. 2005;26:347–62. PubMed

Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see) Nat Rev Immunol. 2014;14:377–91. PubMed PMC

Cano RLE LH. Introduction to T and B lymphocytes. In: Anaya JM SY, Rojas-Villarraga A, et al. Autoimmunity: From Bench to Bedside. Bogota (Colombia): El Rosario University Press. 2013. PubMed

Giannoccaro MP, Gastaldi M, Rizzo G, Jacobson L, Vacchiano V, Perini G. et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain, behavior, and immunity. 2021;96:106–12. PubMed

Jezequel J, Johansson EM, Leboyer M, Groc L. Pathogenicity of Antibodies against NMDA Receptor: Molecular Insights into Autoimmune Psychosis. Trends Neurosci. 2018;41:502–11. PubMed

Jorratt P, Hoschl C, Ovsepian SV. Endogenous antagonists of N-methyl-d-aspartate receptor in schizophrenia. Alzheimers Dement. 2021;17:888–905. PubMed

Hansen N. Current Nosology of Neural Autoantibody-Associated Dementia. Front Aging Neurosci. 2021;13:711195. PubMed PMC

Hansen N, Juhl AL, Grenzer IM, Hirschel S, Teegen B, Fitzner D, Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer's Dementia: A Case-Control Study. Front Immunol. 2022. PubMed PMC

Sun BL, Wang LH, Yang T, Sun JY, Mao LL, Yang MF. et al. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. Prog Neurobiol. 2018;163-164:118–43. PubMed

Ahn JH, Cho H, Kim J-H, Kim SH, Ham J-S, Park I. et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019;572:62–6. PubMed

Hu X, Deng Q, Ma L, Li Q, Chen Y, Liao Y. et al. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res. 2020;30:229–43. PubMed PMC

Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, LeMieux MC, Rufibach K. et al. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009;106:12145–50. PubMed PMC

Kheirkhah R, DeMarshall C, Sieber F, Oh E, Nagele RG. The origin and nature of the complex autoantibody profile in cerebrospinal fluid. Brain Behav Immun Health. 2020;2:100032. PubMed PMC

Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19:771–83. PubMed PMC

Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev. 2019;99:21–78. PubMed PMC

Bartos A, Fialová L, Švarcová J. Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer's Disease. J Alzheimers Dis. 2018;64:751–60. PubMed

Terryberry JW, Thor G, Peter JB. Autoantibodies in Neurodegenerative Diseases: Antigen-Specific Frequencies and Intrathecal Analysis. Neurobiol Aging. 2017;19:205–16. PubMed

Avrameas S, Dighiero G, Lymberi P, Guilbert B. Studies on natural antibodies and autoantibodies. Ann Immunol (Paris) 1983;134d:103–13. PubMed

Poletaev AB, Morozov SG, Gnedenko BB, Zlunikin VM, Korzhenevskey DA. Serum anti-S100b, anti-GFAP and anti-NGF autoantibodies of IgG class in healthy persons and patients with mental and neurological disorders. Autoimmunity. 2000;32:33–8. PubMed

Park H, Kim M, Kim HJ, Lee Y, Seo Y, Pham CD. et al. Heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) function as endocytic receptors for an internalizing anti-nucleic acid antibody. Sci Rep. 2017;7:14373. PubMed PMC

Gaskin F, Finley J, Fang Q, Xu S, Fu SM. Human antibodies reactive with beta-amyloid protein in Alzheimer's disease. J Exp Med. 1993;177:1181–6. PubMed PMC

Baril L, Nicolas L, Croisile B, Crozier P, Hessler C, Sassolas A. et al. Immune response to Aβ-peptides in peripheral blood from patients with Alzheimer's disease and control subjects. Neurosci Lett. 2004;355:226–30. PubMed

Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B. et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology. 2001;57:801–5. PubMed

Hyman BT, Smith C, Buldyrev I, Whelan C, Brown H, Tang M-X. et al. Autoantibodies to amyloid-β and Alzheimer's disease. Ann Neurol. 2001;49:808–10. PubMed

Klaver AC, Coffey MP, Smith LM, Bennett DA, Finke JM, Dang L. et al. ELISA measurement of specific non-antigen-bound antibodies to Aβ1-42 monomer and soluble oligomers in sera from Alzheimer's disease, mild cognitively impaired, and noncognitively impaired subjects. J Neuroinflammation. 2011;8:93. - PubMed PMC

Mruthinti S, Buccafusco JJ, Hill WD, Waller JL, Jackson TW, Zamrini EY, Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Aβ and RAGE peptides. Neurobiol Aging. 2004. 25. PubMed

Nath A, Hall E, Tuzova M, Dobbs M, Jones M, Anderson C. et al. Autoantibodies to amyloid β-peptide (Aβ) are increased in Alzheimer's disease patients and Aβ antibodies can enhance Aβ neurotoxicity. Neuromol Med. 2003;3:29–39. PubMed

Qu B-X, Gong Y, Moore C, Fu M, German DC, Chang L-Y. et al. Beta-Amyloid Auto-antibodies are reduced in Alzheimer's disease. J Neuroimmunol. 2014;274:168–73. PubMed PMC

Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol. 2002. 37. PubMed

Gustaw KA, Garrett MR, Lee H-g, Castellani RJ, Zagorski MG, Prakasam A. et al. Antigen-antibody dissociation in Alzheimer disease: a novel approach to diagnosis. J Neurochem. 2008;106:1350–6. PubMed PMC

Brettschneider S, Morgenthaler NG, Teipel SJ, Fischer-Schulz C, Bürger K, Dodel R. et al. Decreased serum amyloid β1-42 autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid β1-42 peptide. Biol Psychiatry. 2005;57:813–6. PubMed

Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to Redox-modified Oligomeric Aβ Are Attenuated in the Plasma of Alzheimer's Disease Patients. J Biol Chem. 2005;280:17458–63. PubMed

Song MS, Mook-Jung I, Lee HJ, Min JY, Park MH. Serum Anti-Amyloid-β Antibodies and Alzheimer's Disease in Elderly Korean Patients. J Int Med Res. 2007;35:301–6. PubMed

Gruden MA, Davidova TB, Mališauskas M, Sewell RDE, Voskresenskaya NI, Wilhelm K. et al. Differential neuroimmune markers to the onset of Alzheimer's disease neurodegeneration and dementia: Autoantibodies to Aβ(25-35) oligomers, S100b and neurotransmitters. J Neuroimmunol. 2007;186:181–92. PubMed

Millucci L, Ghezzi L, Bernardini G, Santucci A. Conformations and biological activities of amyloid beta peptide 25-35. Curr Protein Pept Sci. 2010;11:54–67. PubMed

Gustaw-Rothenberg KA, Siedlak SL, Bonda DJ, Lerner A, Tabaton M, Perry G. et al. Dissociated amyloid-beta antibody levels as a serum biomarker for the progression of Alzheimer's disease: a population-based study. Exp Gerontol. 2010;45:47–52. PubMed PMC

McMahon MJ, O'Kennedy R. Polyreactivity as an acquired artefact, rather than a physiologic property, of antibodies: evidence that monoreactive antibodies may gain the ability to bind to multiple antigens after exposure to low pH. J Immunol Methods. 2000;241:1–10. PubMed

Maftei M, Thurm F, Schnack C, Tumani H, Otto M, Elbert T. et al. Increased Levels of Antigen-Bound β-Amyloid Autoantibodies in Serum and Cerebrospinal Fluid of Alzheimer's Disease Patients. PLoS One. 2013;8:e68996. PubMed PMC

Li X-W, Li X-X, Liu Q-S, Cheng Y. Blood and Cerebrospinal Fluid Autoantibody to Aβ Levels in Patients with Alzheimer's Disease: a Meta-Analysis Study. J Mol Neurosci. 2020;70:1208–15. PubMed

Itoh N, Arai H, Urakami K, Ishiguro K, Ohno H, Hampel H. et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease. Ann Neurol. 2001;50:150–6. PubMed

Kolarova M, Garcia-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis. 2012;2012:731526. PubMed PMC

Skillbäck T, Farahmand BY, Rosén C, Mattsson N, Nägga K, Kilander L. et al. Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia. Brain. 2015;138:2716–31. PubMed

Bartos A, Fialová L, Švarcová J, Ripova D. Patients with Alzheimer disease have elevated intrathecal synthesis of antibodies against tau protein and heavy neurofilament. J Neuroimmunol. 2012;252:100–5. PubMed

Klaver AC, Coffey MP, Bennett DA, Loeffler DA. Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired, mildly cognitively impaired, and Alzheimer's disease subjects: an exploratory study. Transl Neurodegener. 2017. 6. PubMed PMC

Krestova M, Hromadkova L, Bilkova Z, Bartos A, Ricny J. Characterization of Isolated Tau-Reactive Antibodies From the Ivig Product, Plasma of Patients with Alzheimer's Disease and Cognitively Normal Individuals. J Neuroimmunol. 2017;313:16–24. PubMed

Kuhn I, Rogosch T, Schindler TI, Tackenberg B, Zemlin M, Maier RF. et al. Serum titers of autoantibodies against α-synuclein and tau in child- and adulthood. J Neuroimmunol. 2018;315:33–9. PubMed

Rosenmann H, Meiner Z, Geylis V, Abramsky O, Steinitz M. Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer's disease and healthy subjects. Neurosci Lett. 2006;410:90–3. PubMed

Smith LM, Coffey MP, Klaver AC, Loeffler DA. Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein. Int Immunopharmacol. 2013;16:424–8. PubMed

Hromadkova L, Kolarova M, Jankovicova B, Bartos A, Ricny J, Bilkova Z. et al. Identification and characterization of natural antibodies against tau protein in an intravenous immunoglobulin product. J Neuroimmunol. 2015;289:121–9. PubMed

Smith LM, Coffey MP, Loeffler DA. Specific binding of intravenous immunoglobulin products to tau peptide fragments. Int Immunopharmacol. 2014;21:279–82. PubMed

Levin EC, Acharya NK, Han M, Zavareh SB, Sedeyn JC, Venkataraman V. et al. Brain-reactive autoantibodies are nearly ubiquitous in human sera and may be linked to pathology in the context of blood-brain barrier breakdown. Brain Res. 2010;1345:221–32. PubMed

D'Andrea MR. Evidence that immunoglobulin-positive neurons in Alzheimer's disease are dying via the classical antibody-dependent complement pathway. Am J Alzheimers Dis Other Demen. 2005;20:144–50. PubMed PMC

Bartos A, Stourac P, Rusina R, Sejdová M, Velenská Z. [Paraneoplastic cerebellar degeneration associated with ovarian cancer: anti-Yo immunoreactivity in autoptic cerebellum and ovarian carcinoma] Nervenarzt. 2002;73:995–8. PubMed

Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol. 2010;257:509–17. PubMed

Kronimus Y, Albus A, Balzer-Geldsetzer M, Straub S, Semler E, Otto M. et al. Naturally Occurring Autoantibodies against Tau Protein Are Reduced in Parkinson's Disease Dementia. PLoS One. 2016;11:e0164953. PubMed PMC

Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J Cell Sci. 2000. 113 Pt 21: 3737-45. PubMed

Augustinack JC, Schneider A, Mandelkow EM, Hyman BT. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease. Acta Neuropathol. 2002;103:26–35. PubMed

Berry RW, Abraha A, Lagalwar S, LaPointe N, Gamblin TC, Cryns VL. et al. Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. Biochemistry. 2003;42:8325–31. PubMed

Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW. Tau, tangles, and Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2005;1739:216–23. PubMed

García-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI. Conformational changes and truncation of tau protein during tangle evolution in Alzheimer's disease. J Alzheimers Dis. 2003;5:65–77. PubMed

Hromadkova L, Ovsepian SV. Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer's Disease. J Immunol Res. 2019;2019:7406810. PubMed PMC

Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022. PubMed

Gafson AR, Barthélemy NR, Bomont P, Carare RO, Durham HD, Julien JP. et al. Neurofilaments: neurobiological foundations for biomarker applications. Brain. 2020;143:1975–98. PubMed PMC

Perrot R, Berges R, Bocquet A, Eyer J. Review of the multiple aspects of neurofilament functions, and their possible contribution to neurodegeneration. Molecular neurobiology. 2008;38:27–65. PubMed

Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T. et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14:577–89. PubMed

Trojanowski JQ, Walkenstein N, Lee VM. Expression of neurofilament subunits in neurons of the central and peripheral nervous system: an immunohistochemical study with monoclonal antibodies. J Neurosci. 1986;6:650–60. PubMed PMC

Yuan A, Nixon RA. Specialized roles of neurofilament proteins in synapses: Relevance to neuropsychiatric disorders. Brain Res Bull. 2016;126:334–46. PubMed PMC

Ishii T, Haga S, Tokutake S. Presence of neurofilament protein in Alzheimer's neurofibrillary tangles (ANT). An immunofluorescent study. Acta Neuropathol. 1979;48:105–12. PubMed

Goldman JE, Yen SH, Chiu FC, Peress NS. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983;221:1082–4. PubMed

Delisle MB, Carpenter S. Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J Neurol Sci. 1984;63:241–50. PubMed

Norgren N, Rosengren L, Stigbrand T. Elevated neurofilament levels in neurological diseases. Brain Res. 2003;987:25–31. PubMed

Petzold A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci. 2005;233:183–98. PubMed

Gordon BA. Neurofilaments in disease: what do we know? Curr Opin Neurobiol. 2020;61:105–15. PubMed PMC

Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U. et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017;88:930–7. PubMed PMC

Ashton NJ, Janelidze S, Al Khleifat A, Leuzy A, van der Ende EL, Karikari TK. et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun. 2021;12:3400. PubMed PMC

Fialová L, Bartos A, Svarcová J, Zimova D, Kotoucova J, Malbohan I. Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. J Neuroimmunol. 2013;262:113–20. PubMed

Ehling R, Lutterotti A, Wanschitz J, Khalil M, Gneiss C, Deisenhammer F. et al. Increased frequencies of serum antibodies to neurofilament light in patients with primary chronic progressive multiple sclerosis. Mult Scler. 2004;10:601–6. PubMed

Lu XY, Chen XX, Huang LD, Zhu CQ, Gu YY, Ye S. Anti-alpha-internexin autoantibody from neuropsychiatric lupus induce cognitive damage via inhibiting axonal elongation and promote neuron apoptosis. PLoS One. 2010;5:e11124. PubMed PMC

Oron L, Dubovik V, Perlman M, Novitsky L, Michaelson DM. Model Studies of the Role of Anti-Neurofilament Antibodies in Neurodegeneration in Alzheimer's Disease. Boston, MA: Birkhäuser Boston. 1994. p. 395-401.

Oron L, Dubovik V, Novitsky L, Eilam D, Michaelson DM. Animal model and in vitro studies of anti neurofilament antibodies mediated neurodegeneration in Alzheimer's disease. J Neural Transm Suppl. 1997;49:77–84. PubMed

Stubbs EB Jr, Lawlor MW, Richards MP, Siddiqui K, Fisher MA, Bhoopalam N. et al. Anti-neurofilament antibodies in neuropathy with monoclonal gammopathy of undetermined significance produce experimental motor nerve conduction block. Acta Neuropathol. 2003;105:109–16. PubMed

Soussan L, Tchernakov K, Bachar-Lavi O, Yuvan T, Wertman E, Michaelson DM. Antibodies to different isoforms of the heavy neurofilament protein (NF-H) in normal aging and Alzheimer's disease. Molecular neurobiology. 1994;9:83–91. PubMed

Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211. PubMed

McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D. et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89:88–100. PubMed PMC

Attems J, Toledo JB, Walker L, Gelpi E, Gentleman S, Halliday G. et al. Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study. Acta Neuropathol. 2021;141:159–72. PubMed PMC

Oczkowska A, Kozubski W, Lianeri M, Dorszewska J. Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson's Disease. Curr Genomics. 2013;14:502–17. PubMed PMC

Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM. A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain. 2005;128:2665–74. PubMed

Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A. et al. Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models. J Neurosci. 2014;34:9441–54. PubMed PMC

Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M. et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005;46:857–68. PubMed

Tran HT, Chung CH-Y, Iba M, Zhang B, Trojanowski JQ, Luk KC. et al. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7:2054–65. PubMed PMC

Monahan AJ, Warren M, Carvey PM. Neuroinflammation and Peripheral Immune Infiltration in Parkinson's Disease: An Autoimmune Hypothesis. Cell Transplant. 2008;17:363–72. PubMed

Gruden MA, Sewell RDE, Yanamandra K, Davidova TV, Kucheryanu VG, Bocharov EV. et al. Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression. J Neuroimmunol. 2011;233:221–7. PubMed

Heinzel S, Gold M, Deuschle C, Bernhard F, Maetzler W, Berg D. et al. Naturally occurring alpha-synuclein autoantibodies in Parkinson's disease: sources of (error) variance in biomarker assays. PLoS One. 2014;9:e114566. PubMed PMC

Smith LM, Schiess MC, Coffey MP, Klaver AC, Loeffler DA. α-Synuclein and Anti-α-Synuclein Antibodies in Parkinson's Disease, Atypical Parkinson Syndromes, REM Sleep Behavior Disorder, and Healthy Controls. PLoS One. 2012;7:e52285. PubMed PMC

Woulfe JM, Duke R, Middeldorp JM, Stevens S, Vervoort M, Hashimoto M. et al. Absence of elevated anti-alpha-synuclein and anti-EBV latent membrane protein antibodies in PD. Neurology. 2002;58:1435–6. PubMed

Besong-Agbo D, Wolf E, Jessen F, Oechsner M, Hametner E, Poewe W. et al. Naturally occurring α-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology. 2013;80:169–75. PubMed

Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, Morozova-Roche LA. α-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients. PLoS One. 2011;6:e18513. PubMed PMC

Horvath I, Iashchishyn IA, Forsgren L, Morozova-Roche LA. Immunochemical Detection of α-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels. ACS Chem Neurosci. 2017;8:1170–6. PubMed

Akhtar RS, Licata JP, Luk KC, Shaw LM, Trojanowski JQ, Lee VMY. Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease. J Neurochem. 2018;145:489–503. PubMed PMC

Koehler NKU, Stransky E, Shing M, Gaertner S, Meyer M, Schreitmüller B. et al. Altered Serum IgG Levels to α-Synuclein in Dementia with Lewy Bodies and Alzheimer's Disease. PLoS One. 2013;8:e64649. PubMed PMC

Maetzler W, Berg D, Synofzik M, Brockmann K, Godau J, Melms A. et al. Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. J Alzheimers Dis. 2011;26:171–9. PubMed

Benson GS, Bauer C, Hausner L, Couturier S, Lewczuk P, Peters O, Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network. J Neural Transm (Vienna) 2022. PubMed PMC

Konijnenberg E, Tijms BM, Gobom J, Dobricic V, Bos I, Vos S. et al. APOE epsilon4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease. Alzheimers Res Ther. 2020;12:65. PubMed PMC

Klafki HW, Wirths O, Mollenhauer B, Liepold T, Rieper P, Esselmann H. et al. Detection and quantification of Abeta-3-40 (APP669-711) in cerebrospinal fluid. J Neurochem. 2022;160:578–89. PubMed

Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S. et al. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015;526:443–7. PubMed PMC

Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004;10(Suppl):S10–7. PubMed

D'Atri A, Scarpelli S, Gorgoni M, Truglia I, Lauri G, Cordone S. et al. EEG alterations during wake and sleep in mild cognitive impairment and Alzheimer's disease. iScience. 2021;24:102386. PubMed PMC

Thientunyakit T, Sethanandha C, Muangpaisan W, Chawalparit O, Arunrungvichian K, Siriprapa T. et al. Relationships between amyloid levels, glucose metabolism, morphologic changes in the brain and clinical status of patients with Alzheimer's disease. Ann Nucl Med. 2020;34:337–48. PubMed

Guennewig B, Lim J, Marshall L, McCorkindale AN, Paasila PJ, Patrick E. et al. Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology. Sci Rep. 2021;11:4865. PubMed PMC

Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019;9:8368. PubMed PMC

Dourlen P, Kilinc D, Malmanche N, Chapuis J, Lambert JC. The new genetic landscape of Alzheimer's disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol. 2019;138:221–36. PubMed PMC

Herrmann H, Aebi U. Intermediate Filaments: Structure and Assembly. Cold Spring Harb Perspect Biol. 2016. 8. PubMed PMC

Kadavath H, Jaremko M, Jaremko L, Zweckstetter M. Structure of Tau(267-312) bound to Microtubules. PDB Entry - 2MZ7. 2015.

Ulmer TS, Bax A, Cole NB, Nussbaum RL. Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem. 2005;280:9595–603. PubMed

Vivekanandan S, Brender JR, Lee SY, Ramamoorthy A. A partially folded structure of amyloid-beta(1-40) in an aqueous environment. Biochem Biophys Res Commun. 2011;411:312–6. PubMed PMC

Gruden MA, Davudova TB, Malisauskas M, Zamotin VV, Sewell RD, Voskresenskaya NI. et al. Autoimmune responses to amyloid structures of Abeta(25-35) peptide and human lysozyme in the serum of patients with progressive Alzheimer's disease. Dement Geriatr Cogn Disord. 2004;18:165–71. PubMed

Jianping L, Zhibing Y, Wei Q, Zhikai C, Jie X, Jinbiao L. Low avidity and level of serum anti-Abeta antibodies in Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:127–32. PubMed

Xu W, Kawarabayashi T, Matsubara E, Deguchi K, Murakami T, Harigaya Y. et al. Plasma antibodies to Abeta40 and Abeta42 in patients with Alzheimer's disease and normal controls. Brain Res. 2008;1219:169–79. PubMed

Sohn JH, So JO, Hong HJ, Kim JW, Na DR, Kim M. et al. Identification of autoantibody against beta-amyloid peptide in the serum of elderly. Front Biosci (Landmark Ed) 2009;14:3879–83. PubMed

Maetzler W, Stapf AK, Schulte C, Hauser A-K, Lerche S, Wurster I. et al. Serum and cerebrospinal fluid uric acid levels in lewy body disorders: associations with disease occurrence and amyloid-β pathway. J Alzheimers Dis. 2011;27:119–26. PubMed

Krestova M, Ricny J, Bartos A. Changes in concentrations of tau-reactive antibodies are dependent on sex in Alzheimer's disease patients. J Neuroimmunol. 2018;322:1–8. PubMed

Fialová L, Bartos A, Švarcová J, Malbohan I. Increased Intrathecal High-Avidity Anti-Tau Antibodies in Patients with Multiple Sclerosis. PLoS One. 2011. 6. PubMed PMC

Gruden MA, Yanamandra K, Kucheryanu VG, Bocharova OR, Sherstnev VV, Morozova-Roche LA. et al. Correlation between protective immunity to α-synuclein aggregates, oxidative stress and inflammation. Neuroimmunomodulation. 2012;19:334–42. PubMed

Bryan T, Luo X, Forsgren L, Morozova-Roche LA, Davis JJ. The robust electrochemical detection of a Parkinson's disease marker in whole blood sera. Chem Sci. 2012;3:3468–73.

Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A. et al. Autoantibodies to alpha-synuclein in inherited Parkinson's disease. J Neurochem. 2007;101:749–56. PubMed PMC

Brudek T, Winge K, Folke J, Christensen S, Fog K, Pakkenberg B. et al. Autoimmune antibody decline in Parkinson's disease and Multiple System Atrophy; a step towards immunotherapeutic strategies. Mol Neurodegener. 2017;12:44. PubMed PMC

Caggiu E, Paulus K, Arru G, Piredda R, Sechi GP, Sechi LA. Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease? J Neuroimmunol. 2016;291:110–4. PubMed

Shalash A, Salama M, Makar M, Roushdy T, Elrassas HH, Mohamed W. et al. Elevated Serum α-Synuclein Autoantibodies in Patients with Parkinson's Disease Relative to Alzheimer's Disease and Controls. Front Neurol. 2017;8:720. PubMed PMC

Xu L, Qi X, Duan S, Xie Y, Ren X, Chen G. et al. MicroRNAs: potential biomarkers for disease diagnosis. Biomed Mater Eng. 2014;24:3917–25. PubMed

Molecular Biomarkers of Neuronal Injury in Epilepsy Shared with Neurodegenerative Diseases