{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:39:17Z","timestamp":1790041157442,"version":"4.0.1"},"reference-count":103,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation","award":["#RO2226\/13-1"],"award-info":[{"award-number":["#RO2226\/13-1"]}]},{"name":"German Research Foundation","award":["AFI #16004"],"award-info":[{"award-number":["AFI #16004"]}]},{"name":"German Research Foundation","award":["#01ED1501B"],"award-info":[{"award-number":["#01ED1501B"]}]},{"name":"German Research Foundation","award":["#01ED1501C"],"award-info":[{"award-number":["#01ED1501C"]}]},{"name":"Alzheimer Forschungsinitiative e.V.","award":["#RO2226\/13-1"],"award-info":[{"award-number":["#RO2226\/13-1"]}]},{"name":"Alzheimer Forschungsinitiative e.V.","award":["AFI #16004"],"award-info":[{"award-number":["AFI #16004"]}]},{"name":"Alzheimer Forschungsinitiative e.V.","award":["#01ED1501B"],"award-info":[{"award-number":["#01ED1501B"]}]},{"name":"Alzheimer Forschungsinitiative e.V.","award":["#01ED1501C"],"award-info":[{"award-number":["#01ED1501C"]}]},{"name":"German Federal Department of Education, Science, and Technology, BMBF","award":["#RO2226\/13-1"],"award-info":[{"award-number":["#RO2226\/13-1"]}]},{"name":"German Federal Department of Education, Science, and Technology, BMBF","award":["AFI #16004"],"award-info":[{"award-number":["AFI #16004"]}]},{"name":"German Federal Department of Education, Science, and Technology, BMBF","award":["#01ED1501B"],"award-info":[{"award-number":["#01ED1501B"]}]},{"name":"German Federal Department of Education, Science, and Technology, BMBF","award":["#01ED1501C"],"award-info":[{"award-number":["#01ED1501C"]}]},{"name":"Johannes und Frieda Marohn Foundation","award":["#RO2226\/13-1"],"award-info":[{"award-number":["#RO2226\/13-1"]}]},{"name":"Johannes und Frieda Marohn Foundation","award":["AFI #16004"],"award-info":[{"award-number":["AFI #16004"]}]},{"name":"Johannes und Frieda Marohn Foundation","award":["#01ED1501B"],"award-info":[{"award-number":["#01ED1501B"]}]},{"name":"Johannes und Frieda Marohn Foundation","award":["#01ED1501C"],"award-info":[{"award-number":["#01ED1501C"]}]},{"name":"Research Academy of Leipzig University","award":["#RO2226\/13-1"],"award-info":[{"award-number":["#RO2226\/13-1"]}]},{"name":"Research Academy of Leipzig University","award":["AFI #16004"],"award-info":[{"award-number":["AFI #16004"]}]},{"name":"Research Academy of Leipzig University","award":["#01ED1501B"],"award-info":[{"award-number":["#01ED1501B"]}]},{"name":"Research Academy of Leipzig University","award":["#01ED1501C"],"award-info":[{"award-number":["#01ED1501C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The deposition of \u03b2-amyloid peptides and of \u03b1-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead co-exist and interact with each other. Here, we investigated the presence of a newly identified, pyroglutamate79-modified \u03b1-synuclein variant (pGlu79-aSyn)\u2014along with the enzyme matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation\u2014in AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue. Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we demonstrate an association of pGlu79-aSyn, MMP-3 and QC with \u03b2-amyloid plaques. In addition, pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can be generated extracellularly or within reactive astrocytes, accumulates in proximity to \u03b2-amyloid plaques and induces an astrocytic protein unfolding mechanism involving HSP27.<\/jats:p>","DOI":"10.3390\/biom12071006","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T11:22:24Z","timestamp":1658316144000},"page":"1006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Immunohistochemical Demonstration of the pGlu79 \u03b1-Synuclein Fragment in Alzheimer\u2019s Disease and Its Tg2576 Mouse Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Alexandra","family":"Bluhm","sequence":"first","affiliation":[{"name":"Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Schrempel","sequence":"additional","affiliation":[{"name":"Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schilling","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle (Saale), Germany"},{"name":"Faculty of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, 06366 K\u00f6then, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6409-0664","authenticated-orcid":false,"given":"Stephan","family":"von H\u00f6rsten","sequence":"additional","affiliation":[{"name":"Department for Experimental Therapy, University Clinics Erlangen and Preclinical Experimental Center, University of Erlangen-Nuremberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3358-8299","authenticated-orcid":false,"given":"Anja","family":"Schulze","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Ro\u00dfner","sequence":"additional","affiliation":[{"name":"Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Hartlage-R\u00fcbsamen","sequence":"additional","affiliation":[{"name":"Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41591-020-0781-z","article-title":"A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer\u2019s disease","volume":"26","author":"Barthelemy","year":"2020","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(13)70044-9","article-title":"Amyloid \u00df deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer\u2019s disease: A prospective cohort study","volume":"12","author":"Villemagne","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/ana.410100203","article-title":"Alzheimer\u2019s disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis","volume":"10","author":"Whitehouse","year":"1981","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1126\/science.6338589","article-title":"Alzheimer\u2019s disease: A disorder of cortical cholinergic innervation","volume":"219","author":"Coyle","year":"1983","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/00002093-198701040-00005","article-title":"Neuronal degeneration in the locus coeruleus and cortical correlates of Alzheimer\u2019s disease","volume":"1","author":"Bondareff","year":"1987","journal-title":"Alzheimer Dis. Assoc. Discord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0197-4580(97)00035-3","article-title":"Spatial, temporal and numeric analysis of Alzheimer changes in the nucleus coeruleus","volume":"18","author":"Busch","year":"1997","journal-title":"Neurobiol. Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"342","DOI":"10.2174\/156720508784533286","article-title":"Functional consequences of locus coeruleus degeneration in Alzheimer\u2019s disease","volume":"5","author":"Weinshenker","year":"2008","journal-title":"Curr. Alzheimer. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1016\/S0042-6989(01)00090-6","article-title":"The premotor region essential for rapid vertical eye movements shows early involvement in Alzheimer\u2019s disease-related cytoskeletal pathology","volume":"41","author":"Schultz","year":"2001","journal-title":"Vis. Res"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s004010051031","article-title":"Focal pathology in Edinger-Westphal nucleus explains pupillary hypersensitivity in Alzheimer\u2019s disease","volume":"97","author":"Scinto","year":"1999","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0197-4580(01)00235-4","article-title":"Selective cell loss in Edinger-Westphal in asymptomatic elders and Alzheimer\u2019s patients","volume":"22","author":"Scinto","year":"2001","journal-title":"Neurobiol. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S209","DOI":"10.1016\/S1353-8020(09)70816-8","article-title":"Iron transport in Parkinson\u2019s disease","volume":"15","author":"Hirsch","year":"2009","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10992","DOI":"10.1074\/jbc.M709634200","article-title":"Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers","volume":"283","author":"Kostka","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29739","DOI":"10.1074\/jbc.M600933200","article-title":"Phosphorylation of Ser-129 is the dominant pathological modification of \u03b1-synuclein in familial and sporadic Lewy body disease","volume":"281","author":"Anderson","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.mcn.2013.01.004","article-title":"Oxidative stress-induced posttranslational modifications of alpha-synuclein: Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity","volume":"54","author":"Xiang","year":"2013","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1093\/brain\/awx056","article-title":"Glycation potentiates \u03b1-synuclein-associated neurodegeneration in synucleinopathies","volume":"140","author":"Szego","year":"2017","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1111\/jnc.14721","article-title":"Effects of alpha-synuclein post-translational modifications on metal binding","volume":"150","author":"Quintanar","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.expneurol.2008.04.001","article-title":"Cortico-basal ganglia-cortical circuitry in Parkinson\u2019s disease reconsidered","volume":"212","author":"Braak","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/j.clinph.2008.03.017","article-title":"Pathophysiology of Parkinsonism","volume":"119","author":"Galvan","year":"2008","journal-title":"Clin. Neurophysiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/nm.1872","article-title":"Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer\u2019s disease-like pathology","volume":"14","author":"Schilling","year":"2008","journal-title":"Nature Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s00401-021-02349-5","article-title":"A glutaminyl cyclase-catalyzed alpha-synuclein modification identified in human synucleinopathies","volume":"142","author":"Bluhm","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1177\/10454411930040020401","article-title":"Matrix metalloproteinases: A review","volume":"4","author":"Moore","year":"1993","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Madzharova, E., Kastl, P., Sabino, F., and auf dem Keller, U. (2019). Post-translational modification-dependent activity of matrix metalloproteinases. Int. J. Molec. Sci., 20.","DOI":"10.3390\/ijms20123077"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1471-4159.2010.07082.x","article-title":"Role of matrix metalloproteinase-3 in neurodegeneration","volume":"116","author":"Kim","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25216","DOI":"10.1074\/jbc.M503341200","article-title":"Proteolytic cleavage of extracellular secreted alpha-synuclein via matrix metalloproteinases","volume":"280","author":"Sung","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.expneurol.2008.10.010","article-title":"Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases","volume":"215","author":"Levin","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bluhm, A., Schrempel, S., von H\u00f6rsten, S., Schulze, A., and Ro\u00dfner, S. (2021). Proteolytic \u03b1-synuclein cleavage in health and disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115450"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1365-2826.1995.tb00780.x","article-title":"Glutaminyl-cyclase expression in the bovine\/porcine hypothalamus and pituitary","volume":"7","author":"Kreutz","year":"1995","journal-title":"J. Neuroendocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8532","DOI":"10.1016\/S0021-9258(18)47446-7","article-title":"An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides","volume":"262","author":"Busby","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1073\/pnas.84.11.3628","article-title":"Identification of a mammalian glutaminyl cyclase converting glutaminyl into pyroglutamyl peptides","volume":"84","author":"Fischer","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10059","DOI":"10.1073\/pnas.88.22.10059","article-title":"Primary structure and functional expression of a glutaminyl cyclase","volume":"88","author":"Pohl","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.ijdevneu.2009.08.007","article-title":"Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain","volume":"27","author":"Staffa","year":"2009","journal-title":"Int. J. Devl. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00401-011-0806-2","article-title":"Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-A\u03b2 deposits in hippocampus via distinct cellular mechanisms","volume":"121","author":"Morawski","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3233\/JAD-131535","article-title":"Glutaminyl cyclase in human cortex: Correlation with (pGlu)-amyloid-\u03b2 load and cognitive decline in Alzheimer\u2019s disease","volume":"39","author":"Morawski","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00401-010-0685-y","article-title":"Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-A\u03b2 pathology in Alzheimer\u2019s disease","volume":"120","author":"Morawski","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nature11060","article-title":"Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-\u03b2","volume":"485","author":"Nussbaum","year":"2012","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1159\/000121389","article-title":"Association between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt-Jakob disease","volume":"5","author":"Debatin","year":"2008","journal-title":"Neurodegener Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s004010000271","article-title":"Prion protein expression in senile plaques in Alzheimer\u2019s disease","volume":"101","author":"Ferrer","year":"2001","journal-title":"Acta Neuropathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s004010050870","article-title":"Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease","volume":"96","author":"Hainfeller","year":"1998","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/j.1750-3639.2000.tb00269.x","article-title":"Lewy bodies in Alzheimer\u2019s disease: A neuropathological review of 145 cases using \u03b1-synuclein immunohistochemistry","volume":"10","author":"Hamilton","year":"2000","journal-title":"Brain Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1901","article-title":"Transmission and spreading of tauopathy in transgenic mouse brain","volume":"11","author":"Clavaguera","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1523\/JNEUROSCI.20-10-03606.2000","article-title":"Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice","volume":"20","author":"Kane","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20051","DOI":"10.1073\/pnas.0908005106","article-title":"Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells","volume":"106","author":"Luk","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nn2058","article-title":"A molecular pathway of neurodegeneration linking \u03b1-synuclein to APOE and A\u03b2 peptides","volume":"11","author":"Gallardo","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s00401-007-0336-0","article-title":"Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson\u2019s disease patients","volume":"115","author":"Lashley","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"K\u00f6ppen, J., Schulze, A., Machner, L., Wermann, M., Eichentopf, R., Guthardt, M., H\u00e4hnel, A., Klehm, J., Kriegeskorte, M., and Hartlage-R\u00fcbsamen, M. (2020). Amyloid-beta peptides trigger aggregation of alpha-synuclein by in vitro. Molecules, 25.","DOI":"10.3390\/molecules25030580"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12245","DOI":"10.1073\/pnas.211412398","article-title":"\u03b2-Amyloid peptides enhance \u03b1-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer\u2019s disease and Parkinson\u2019s disease","volume":"98","author":"Masliah","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Tsigelny, I.F., Crews, L., Desplats, P., Shaked, G.M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., and Platoshyn, O. (2008). Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer\u2019s and Parkinson\u2019s diseases. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003135"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1523\/JNEUROSCI.0490-10.2010","article-title":"Synergistic interactions between A\u00df, Tau, and \u03b1-synuclein: Acceleration of neuropathology and cognitive decline","volume":"30","author":"Clinton","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_50","first-page":"201","article-title":"Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer\u2019s disease","volume":"148","author":"Masliah","year":"1996","journal-title":"Am. J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1097\/00001756-200011270-00029","article-title":"Lewy body variant of Alzheimer\u2019s disease: Alpha-synuclein in dystrophic neurites of A beta plaques","volume":"11","author":"Wirths","year":"2000","journal-title":"Neuroreport"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neuron.2019.10.010","article-title":"Amyloid-beta (A\u03b2) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with A\u03b2. pathology","volume":"105","author":"Bassil","year":"2020","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0006-8993(99)02207-6","article-title":"Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein","volume":"853","author":"Yang","year":"2000","journal-title":"Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.immuni.2019.03.016","article-title":"Immune signaling in neurodegeneration","volume":"50","author":"Hammond","year":"2019","journal-title":"Immunity"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s40478-017-0478-9","article-title":"Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions","volume":"5","author":"Gerber","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13024-017-0192-x","article-title":"Glial contributions to neurodegeneration in tauopathies","volume":"12","author":"Leyns","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s00401-011-0833-z","article-title":"Glial dysfunction in the pathogenesis of \u03b1-synucleinopathies: Emerging concepts","volume":"121","author":"Fellner","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/glia.10178","article-title":"Astrocytic expression of the Alzheimer\u2019s disease beta-secretase (BACE1) is stimulus-dependent","volume":"41","author":"Zeitschel","year":"2003","journal-title":"Glia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S1016-8478(23)07364-8","article-title":"Heat shock responses for understanding diseases of protein denaturation","volume":"23","author":"Kim","year":"2007","journal-title":"Mol. Cells"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/sj.emboj.7601970","article-title":"Chaperones in control of protein disaggregation","volume":"27","author":"Liberek","year":"2008","journal-title":"EMBO J."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Navarro-Zaragoza, J., Cuenca-Bermejo, L., Almela, P., Laorden, M.L., and Herrero, M.T. (2021). Could small heat shock protein HSP27 be a first-line target for preventing protein aggregation in Parkinson\u2019s disease?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063038"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s12192-013-0428-9","article-title":"Overexpression of Hsp27 ameliorates symptoms of Alzheimer\u2019s disease in APP\/PS1 mice","volume":"18","author":"Szegedi","year":"2013","journal-title":"Cell Stress Chaperones"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.bbrc.2006.06.128","article-title":"Small heat shock proteins differentially affect Abeta aggregation and toxicity","volume":"347","author":"Lee","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1016\/j.bbadis.2014.06.024","article-title":"Preventing \u03b1-synuclein aggregation: The role of the small heat-shock molecular chaperone proteins","volume":"1842","author":"Cox","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Hartlage-R\u00fcbsamen, M., Bluhm, A., Piechotta, A., Linnert, M., Rahfeld, J.U., Demuth, H.U., Lues, I., Kuhn, P.H., Lichtenthaler, S.F., and Ro\u00dfner, S. (2018). Immunohistochemical evidence from APP-transgenic mice for glutaminyl cyclase as drug target to diminish pE-Abeta formation. Molecules, 23.","DOI":"10.3390\/molecules23040924"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1126\/science.274.5284.99","article-title":"Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice","volume":"274","author":"Hsiao","year":"1996","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"ref_69","unstructured":"The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer\u2019s Disease (1997). Consensus recommendations for the postmortem diagnosis of Alzheimer\u2019s disease. Neurobiol. Aging, 18, S1\u2013S2."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s00401-015-1406-3","article-title":"Neuropathologically mixed Alzheimer\u2019s and Lewy body disease: Burden of pathological protein aggregates differs between clinical phenotypes","volume":"129","author":"Walker","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1021\/acs.biochem.9b00655","article-title":"Interactions between soluble species of beta-amyloid and alpha-synuclein promote oligomerization while inhibiting fibrillization","volume":"59","author":"Candreva","year":"2020","journal-title":"Biochemistry"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"777706","DOI":"10.3389\/fnsys.2021.777706","article-title":"It is time to study overlapping molecular and circuit pathophysiologies in Alzheimer\u2019s and Lewy body disease spectra","volume":"15","author":"Wakasugi","year":"2021","journal-title":"Front. Syst. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s11064-006-9140-9","article-title":"Interaction between Abeta peptide and \u03b1-synuclein: Molecular mechanisms in overlapping pathology of Alzheimer\u2019s and Parkinson\u2019s in dementia with Lewy bodies","volume":"31","author":"Mandal","year":"2006","journal-title":"Neurochem. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/nm.3885","article-title":"Inhibition of amyloid-\u03b2 plaque formation by \u03b1-synuclein","volume":"21","author":"Bachhuber","year":"2015","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"11282","DOI":"10.1073\/pnas.90.23.11282","article-title":"Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease","volume":"90","author":"Fukushima","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0304-3940(99)00311-0","article-title":"Alpha-synuclein accumulates in Lewy bodies in Parkinson\u2019s disease and dementia with Lewy bodies but not in Alzheimer\u2019s disease beta-amyloid plaque cores","volume":"266","author":"Bayer","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/S0002-9440(10)65220-0","article-title":"Non-Abeta component of Alzheimer\u2019s disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid","volume":"155","author":"Culvenor","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0278-5846(02)00339-1","article-title":"\u03b1-synuclein, A\u03b2 and Alzheimer\u2019s disease","volume":"27","author":"Wirths","year":"2003","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1002\/glia.23981","article-title":"Reactive astrocytes as treatment targets in Alzheimer\u2019s disease-Systematic review of studies using the APPswePS1dE9 mouse model","volume":"69","author":"Smit","year":"2021","journal-title":"Glia"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wang, P., and Ye, Y. (2021). Astrocytes in neurodegenerative diseases: A perspective from tauopathy and a-synucleinopathy. Life, 11.","DOI":"10.3390\/life11090938"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/glia.24109","article-title":"Astrocytic VEGFA: An essential mediator in blood-brain-barrier disruption in Parkinson\u2019s disease","volume":"70","author":"Lan","year":"2022","journal-title":"Glia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00401-007-0244-3","article-title":"Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson\u2019s disease","volume":"114","author":"Braak","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/PL00007400","article-title":"NACP\/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson\u2019s disease brains","volume":"99","author":"Wakabayashi","year":"2000","journal-title":"Acta Neuropathol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1097\/NEN.0b013e3181b66f1b","article-title":"Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression","volume":"68","author":"Song","year":"2009","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1042\/BCJ20180297","article-title":"Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons","volume":"475","author":"Quijano","year":"2018","journal-title":"Biochem. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1756-6606-3-12","article-title":"Astrocytic expression of Parkinson\u2019s disease-related A53T alpha-synuclein causes neurodegeneration in mice","volume":"3","author":"Gu","year":"2010","journal-title":"Molec. Brain"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"9262","DOI":"10.1074\/jbc.M109.081125","article-title":"Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies","volume":"285","author":"Lee","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s40478-020-00983-w","article-title":"Erythrocytic \u03b1-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: A new perspective on Parkinson\u2019s disease pathogenesis","volume":"8","author":"Sheng","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"10865","DOI":"10.1073\/pnas.1918617117","article-title":"A myosin-7B-dependent endocytosis pathway mediates cellular entry of alpha-synuclein fibrils and polycation-bearing cargos","volume":"117","author":"Zhang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"11835","DOI":"10.1523\/JNEUROSCI.0983-17.2017","article-title":"Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes","volume":"37","author":"Rostami","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s00401-017-1746-2","article-title":"Alpha-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading","volume":"134","author":"Loria","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.bbadis.2014.11.011","article-title":"Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes","volume":"1852","author":"Waniek","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.febslet.2004.08.062","article-title":"Transglutaminase catalyzes differential crosslinking of small heat shock proteins and amyloid-beta","volume":"576","author":"Boros","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.neuint.2019.01.021","article-title":"Novel compound VB-037 inhibits Abeta aggregation and promotes neurite outgrowth through enhancement of HSP27 and reduction of P38 and JNK-mediated inflammation in cell models for Alzheimer\u2019s disease","volume":"125","author":"Chiu","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1365-2990.2006.00689.x","article-title":"Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer\u2019s disease brains","volume":"32","author":"Wilhelmus","year":"2006","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3233\/JAD-150317","article-title":"Astrocytes release HspB1 in response to amyloid-\u03b2 exposure in vitro","volume":"49","author":"Nafar","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1128\/MCB.01187-10","article-title":"Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism","volume":"31","author":"Ojha","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s00018-016-2340-9","article-title":"Expanding role of molecular chaperones in regulating \u03b1-synuclein misfolding; implications in Parkinson\u2019s disease","volume":"74","author":"Sharma","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1002\/prot.23152","article-title":"Inhibition of \u03b1-synuclein aggregation by small heat shock proteins","volume":"79","author":"Bruinsma","year":"2011","journal-title":"Proteins"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1046\/j.1471-4159.2003.02273.x","article-title":"HSP27 but not HSP70 has a potent protective effect against alpha-synuclein-induced cell death in mammalian neuronal cells","volume":"88","author":"Zourlidou","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4486","DOI":"10.1074\/jbc.M117.813865","article-title":"The small heat shock protein Hsp27 binds \u03b1-synuclein fibrils, preventing elongation and cytotoxicity","volume":"293","author":"Cox","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.bbrc.2006.10.085","article-title":"Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation","volume":"351","author":"Outeiro","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6718","DOI":"10.1096\/fj.201902936R","article-title":"Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein","volume":"34","author":"Oliveira","year":"2020","journal-title":"FASEB J."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/7\/1006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:54:35Z","timestamp":1760140475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/7\/1006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,20]]},"references-count":103,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["biom12071006"],"URL":"https:\/\/doi.org\/10.3390\/biom12071006","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,20]]}}}