The transcellular propagation of the aberrantly modified protein tau along the functional brain network is a key hallmark of Alzheimer's disease and related tauopathies. Inoculation-based tau propagation models can recapitulate the stereotypical spread of tau and reproduce various types of tau inclusions linked to specific tauopathy, albeit with varying degrees of fidelity. With this systematic review, we underscore the significance of judicious selection and meticulous functional, biochemical, and biophysical characterization of various tau inocula. Furthermore, we highlight the necessity of choosing suitable animal models and inoculation sites, along with the critical need for validation of fibrillary pathology using confirmatory staining, to accurately recapitulate disease-specific inclusions. As a practical guide, we put forth a framework for establishing a benchmark of inoculation-based tau propagation models that holds promise for use in preclinical testing of disease-modifying drugs.

AXON Neuroscience R and D Services SE Dubravska Cesta 9 845 10 Bratislava Slovakia

Biomedical Research Institute BIOMED Hasselt University 3500 Hasselt Belgium

CEITEC Masaryk University Kamenice 5 625 00 Brno Czech Republic

CNRS EMR9002 BSI Integrative Structural Biology 59000 Lille France

Department of Chemistry Faculty of Science Masaryk University Kamenice 5 62500 Brno Czech Republic

Einstein Center for Neurosciences Berlin Charité Universitätsmedizin Berlin Berlin Germany

Faculty of Medicine Laboratory of Histology Alzheimer and Other Tauopathies Research Group Université Libre de Bruxelles 808 Route de Lennik 1070 Brussels Belgium

German Center for Neurodegenerative Diseases Charitéplatz 1 10117 Berlin Germany

Inserm CHU Lille CNRS LilNCog Lille Neuroscience and Cognition University of Lille 59000 Lille France

Inserm CHU Lille Institut Pasteur de Lille U1167 RID AGE Risk Factors and Molecular Determinants of Aging Related Diseases University of Lille 59000 Lille France

Institute of Neuroimmunology Slovak Academy of Sciences Dubravska Cesta 9 845 10 Bratislava Slovakia

School of Biological Sciences Faculty of Environment and Life Sciences University of Southampton Highfield Campus Southampton SO17 1BJ UK

Zobrazit více v PubMed

Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S, et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014;127:667–683. doi: 10.1007/s00401-014-1254-6. PubMed DOI PMC

Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, et al. Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium. Brain Pathol. 2008;18:484–496. doi: 10.1111/j.1750-3639.2008.00147.x. PubMed DOI PMC

Alafuzoff I, Pikkarainen M, Al-Sarraj S, Arzberger T, Bell J, Bodi I, Bogdanovic N, Budka H, Bugiani O, Ferrer I, et al. Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol. 2006;65:740–757. doi: 10.1097/01.jnen.0000229986.17548.27. PubMed DOI

Albert M, Mairet-Coello G, Danis C, Lieger S, Caillierez R, Carrier S, Skrobala E, Landrieu I, Michel A, Schmitt M, et al. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain. 2019;142:1736–1750. doi: 10.1093/brain/awz100. PubMed DOI PMC

Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci. 2002;22:9340–9351. doi: 10.1523/JNEUROSCI.22-21-09340.2002. PubMed DOI PMC

Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003;86:582–590. doi: 10.1046/j.1471-4159.2003.01879.x. PubMed DOI

Andres-Benito P, Carmona M, Jordan M, Fernandez-Irigoyen J, Santamaria E, Del Rio JA, Ferrer I. Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum. Int J Mol Sci. 2022 doi: 10.3390/ijms23020718. PubMed DOI PMC

Aoyagi A, Condello C, Stohr J, Yue W, Rivera BM, Lee JC, Woerman AL, Halliday G, van Duinen S, Ingelsson M, et al. Abeta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain. Sci Transl Med. 2019 doi: 10.1126/scitranslmed.aat8462. PubMed DOI PMC

Argyrousi EK, Staniszewski A, Nicholls RE, Arancio O. Preparation of tau oligomers after the protein extraction from bacteria and brain cortices. Methods Mol Biol. 2018;1779:85–97. doi: 10.1007/978-1-4939-7816-8_7. PubMed DOI PMC

Asada A, Yamamoto N, Gohda M, Saito T, Hayashi N, Hisanaga S. Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes. J Neurochem. 2008;106:1325–1336. doi: 10.1111/j.1471-4159.2008.05500.x. PubMed DOI

Audouard E, Houben S, Masaracchia C, Yilmaz Z, Suain V, Authelet M, De Decker R, Buee L, Boom A, Leroy K, et al. High-molecular-weight paired helical filaments from alzheimer brain induces seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am J Pathol. 2016;186:2709–2722. doi: 10.1016/j.ajpath.2016.06.008. PubMed DOI

Aulston B, Liu Q, Mante M, Florio J, Rissman RA, Yuan SH. Extracellular vesicles isolated from familial Alzheimer's disease neuronal cultures induce aberrant tau phosphorylation in the wild-type mouse brain. J Alzheimers Dis. 2019;72:575–585. doi: 10.3233/JAD-190656. PubMed DOI PMC

Baker S, Polanco JC, Gotz J. Extracellular vesicles containing P301L mutant tau accelerate pathological tau phosphorylation and oligomer formation but do not seed mature neurofibrillary tangles in ALZ17 mice. J Alzheimers Dis. 2016;54:1207–1217. doi: 10.3233/JAD-160371. PubMed DOI

Balietti M, Pugliese A, Conti F. In aged rats, differences in spatial learning and memory influence the response to late-life environmental enrichment. Exp Gerontol. 2021;146:111225. doi: 10.1016/j.exger.2020.111225. PubMed DOI

Bassil F, Meymand ES, Brown HJ, Xu H, Cox TO, Pattabhiraman S, Maghames CM, Wu Q, Zhang B, Trojanowski JQ, et al. Alpha-Synuclein modulates tau spreading in mouse brains. J Exp Med. 2021 doi: 10.1084/jem.20192193. PubMed DOI PMC

Bellingham SA, Guo BB, Coleman BM, Hill AF. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol. 2012;3:124. doi: 10.3389/fphys.2012.00124. PubMed DOI PMC

Bellucci A, Bugiani O, Ghetti B, Spillantini MG. Presence of reactive microglia and neuroinflammatory mediators in a case of frontotemporal dementia with P301S mutation. Neurodegener Dis. 2011;8:221–229. doi: 10.1159/000322228. PubMed DOI PMC

Bertram L, Tanzi RE. The genetics of Alzheimer's disease. Prog Mol Biol Transl Sci. 2012;107:79–100. doi: 10.1016/b978-0-12-385883-2.00008-4. PubMed DOI

Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains. Acta Neuropathol. 2015;129:221–237. doi: 10.1007/s00401-014-1373-0. PubMed DOI PMC

Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112:389–404. doi: 10.1007/s00401-006-0127-z. PubMed DOI PMC

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/BF00308809. PubMed DOI

Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–278. doi: 10.1016/0197-4580(95)00021-6. PubMed DOI

Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70:960–969. doi: 10.1097/NEN.0b013e318232a379. PubMed DOI

Bubu OM, Pirraglia E, Andrade AG, Sharma RA, Gimenez-Badia S, Umasabor-Bubu OQ, Hogan MM, Shim AM, Mukhtar F, Sharma N, et al. Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes. Sleep. 2019 doi: 10.1093/sleep/zsz048. PubMed DOI PMC

Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33:95–130. doi: 10.1016/s0165-0173(00)00019-9. PubMed DOI

Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Kayed R. Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis. 2014;40(Suppl 1):S97–S111. doi: 10.3233/JAD-132477. PubMed DOI

Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005;280:40364–40374. doi: 10.1074/jbc.M509329200. PubMed DOI

Chung DC, Roemer S, Petrucelli L, Dickson DW. Cellular and pathological heterogeneity of primary tauopathies. Mol Neurodegener. 2021;16:57. doi: 10.1186/s13024-021-00476-x. PubMed DOI PMC

Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–9540. doi: 10.1073/pnas.1301175110. PubMed DOI PMC

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–913. doi: 10.1038/ncb1901. PubMed DOI PMC

Collier JJ, Suomi F. Emerging roles of ATG7 in human health and disease. EMBO Mole Med. 2021;13:e14824. doi: 10.15252/emmm.202114824. PubMed DOI PMC

Cornblath EJ, Li HL, Changolkar L, Zhang B, Brown HJ, Gathagan RJ, Olufemi MF, Trojanowski JQ, Bassett DS, Lee VMY, et al. Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor. Sci Adv. 2021 doi: 10.1126/sciadv.abg6677. PubMed DOI PMC

Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement (N Y) 2023;9:e12385. doi: 10.1002/trc2.12385. PubMed DOI PMC

Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K. Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3x Tg-AD mice. Alzheimers Res Ther. 2018;10:13. doi: 10.1186/s13195-018-0341-7. PubMed DOI PMC

Danis C, Dupre E, Zejneli O, Caillierez R, Arrial A, Begard S, Mortelecque J, Eddarkaoui S, Loyens A, Cantrelle FX, et al. Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Mol Ther. 2022;30:1484–1499. doi: 10.1016/j.ymthe.2022.01.009. PubMed DOI PMC

de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012;73:685–697. doi: 10.1016/j.neuron.2011.11.033. PubMed DOI PMC

Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, Ghozali F, Fallet-Bianco C, Pasquier F, Lebert F, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology. 1999;52:1158–1165. doi: 10.1212/wnl.52.6.1158. PubMed DOI

Detrez JR, Maurin H, Van Kolen K, Willems R, Colombelli J, Lechat B, Roucourt B, Van Leuven F, Baatout S, Larsen P, et al. Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain. Neurobiol Dis. 2019;127:398–409. doi: 10.1016/j.nbd.2019.03.010. PubMed DOI

Diner I, Nguyen T, Seyfried NT. Enrichment of detergent-insoluble protein aggregates from human postmortem brain. J Vis Exp. 2017 doi: 10.3791/55835. PubMed DOI PMC

Dominguez-Meijide A, Vasili E, Outeiro TF. Pharmacological modulators of Tau aggregation and spreading. Brain Sci. 2020 doi: 10.3390/brainsci10110858. PubMed DOI PMC

Dosunmu R, Wu J, Basha R, Zawia N. Environmental and dietary risk factors in Alzheimer’s disease. Expert Rev Neurother. 2007;7:887–900. doi: 10.1586/14737175.7.7.887. PubMed DOI

Dujardin S, Commins C, Lathuiliere A, Beerepoot P, Fernandes AR, Kamath TV, De Los Santos MB, Klickstein N, Corjuc DL, Corjuc BT, et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease. Nat Med. 2020;26:1256–1263. doi: 10.1038/s41591-020-0938-9. PubMed DOI PMC

Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SHW, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018;561:137–140. doi: 10.1038/s41586-018-0454-y. PubMed DOI PMC

Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW, Goedert M. Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol. 2018;136:699–708. doi: 10.1007/s00401-018-1914-z. PubMed DOI PMC

Ferrer I, Aguilo Garcia M, Carmona M, Andres-Benito P, Torrejon-Escribano B, Garcia-Esparcia P, Del Rio JA. Involvement of oligodendrocytes in Tau seeding and spreading in tauopathies. Front Aging Neurosci. 2019;11:112. doi: 10.3389/fnagi.2019.00112. PubMed DOI PMC

Ferrer I, Andres-Benito P, Carmona M, Del Rio JA. Common and specific marks of different tau strains following intra-hippocampal injection of AD, PiD, and GGT inoculum in hTau transgenic mice. Int J Mol Sci. 2022 doi: 10.3390/ijms232415940. PubMed DOI PMC

Ferrer I, Andres-Benito P, Garcia-Esparcia P, Lopez-Gonzalez I, Valiente D, Jordan-Pirla M, Carmona M, Sala-Jarque J, Gil V, Del Rio JA. Differences in Tau seeding in newborn and adult wild-type mice. Int J Mol Sci. 2022 doi: 10.3390/ijms23094789. PubMed DOI PMC

Ferrer I, Andres-Benito P, Sala-Jarque J, Gil V, Del Rio JA. Capacity for seeding and spreading of argyrophilic grain disease in a wild-type murine model; comparisons with primary age-related tauopathy. Front Mol Neurosci. 2020;13:101. doi: 10.3389/fnmol.2020.00101. PubMed DOI PMC

Ferrer I, Andres-Benito P, Zelaya MV, Aguirre MEE, Carmona M, Ausin K, Lachen-Montes M, Fernandez-Irigoyen J, Santamaria E, Del Rio JA. Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy. Acta Neuropathol. 2020;139:735–771. doi: 10.1007/s00401-019-02122-9. PubMed DOI PMC

Fichou Y, Al-Hilaly YK, Devred F, Smet-Nocca C, Tsvetkov PO, Verelst J, Winderickx J, Geukens N, Vanmechelen E, Perrotin A, et al. The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention? Acta Neuropathol Commun. 2019;7:31. doi: 10.1186/s40478-019-0682-x. PubMed DOI PMC

Filipcik P, Zilka N, Bugos O, Kucerak J, Koson P, Novak P, Novak M. First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging. 2012;33:1448–1456. doi: 10.1016/j.neurobiolaging.2010.10.015. PubMed DOI

Fordyce DE, Wehner JM. Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. Brain Res. 1993;619:111–119. doi: 10.1016/0006-8993(93)91602-O. PubMed DOI

Franzmeier N, Brendel M, Beyer L, Slemann L, Kovacs GG, Arzberger T, Kurz C, Respondek G, Lukic MJ, Biel D, et al. Tau deposition patterns are associated with functional connectivity in primary tauopathies. Nat Commun. 2022;13:1362. doi: 10.1038/s41467-022-28896-3. PubMed DOI PMC

Franzmeier N, Neitzel J, Rubinski A, Smith R, Strandberg O, Ossenkoppele R, Hansson O, Ewers M, Alzheimer's Disease Neuroimaging I. Functional brain architecture is associated with the rate of tau accumulation in Alzheimer's disease. Nat Commun. 2020;11:347. doi: 10.1038/s41467-019-14159-1. PubMed DOI PMC

Franzmeier N, Rubinski A, Neitzel J, Kim Y, Damm A, Na DL, Kim HJ, Lyoo CH, Cho H, Finsterwalder S, et al. Functional connectivity associated with tau levels in ageing, Alzheimer's, and small vessel disease. Brain. 2019;142:1093–1107. doi: 10.1093/brain/awz026. PubMed DOI PMC

Fridmacher V, Kaltschmidt B, Goudeau B, Ndiaye D, Rossi FM, Pfeiffer J, Kaltschmidt C, Israël A, Mémet S. Forebrain-specific neuronal inhibition of nuclear factor-kappaB activity leads to loss of neuroprotection. J Neurosci: Off J Soci Neurosci. 2003;23:9403–9408. doi: 10.1523/jneurosci.23-28-09403.2003. PubMed DOI PMC

Gao YL, Wang N, Sun FR, Cao XP, Zhang W, Yu JT. Tau in neurodegenerative disease. Ann Transl Med. 2018;6:175. doi: 10.21037/atm.2018.04.23. PubMed DOI PMC

Gibbons GS, Banks RA, Kim B, Xu H, Changolkar L, Leight SN, Riddle DM, Li C, Gathagan RJ, Brown HJ, et al. GFP-mutant human tau transgenic mice develop tauopathy following CNS injections of Alzheimer's brain-derived pathological tau or synthetic mutant human tau fibrils. J Neurosci. 2017;37:11485–11494. doi: 10.1523/JNEUROSCI.2393-17.2017. PubMed DOI PMC

Gibbons GS, Kim SJ, Robinson JL, Changolkar L, Irwin DJ, Shaw LM, Lee VM, Trojanowski JQ. Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau) Acta Neuropathol Commun. 2019;7:34. doi: 10.1186/s40478-019-0687-5. PubMed DOI PMC

Gibbons GS, Kim SJ, Wu Q, Riddle DM, Leight SN, Changolkar L, Xu H, Meymand ES, O'Reilly M, Zhang B, et al. Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer's disease. Mol Neurodegener. 2020;15:64. doi: 10.1186/s13024-020-00404-5. PubMed DOI PMC

Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010;33:317–325. doi: 10.1016/j.tins.2010.04.003. PubMed DOI

Goedert M, Jakes R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 1990;9:4225–4230. doi: 10.1002/j.1460-2075.1990.tb07870.x. PubMed DOI PMC

Gomez S, Lopez-Estepa M, Fernandez FJ, Suarez T, Vega MC. Alternative eukaryotic expression systems for the production of proteins and protein complexes. Adv Exp Med Biol. 2016;896:167–184. doi: 10.1007/978-3-319-27216-0_11. PubMed DOI

Gozal YM, Duong DM, Gearing M, Cheng D, Hanfelt JJ, Funderburk C, Peng J, Lah JJ, Levey AI Proteomics analysis reveals novel components in the detergent-insoluble subproteome in Alzheimer's disease. J Proteome Res. 2009;8:5069–5079. doi: 10.1021/pr900474t. PubMed DOI PMC

Gratuze M, Chen Y, Parhizkar S, Jain N, Strickland MR, Serrano JR, Colonna M, Ulrich JD, Holtzman DM. Activated microglia mitigate Abeta-associated tau seeding and spreading. J Exp Med. 2021 doi: 10.1084/jem.20210542. PubMed DOI PMC

Guo H, Callaway JB, Ting JPY. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–687. doi: 10.1038/nm.3893. PubMed DOI PMC

Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, Gathagan RJ, Iba M, McBride JD, Trojanowski JQ, et al. Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016;213:2635–2654. doi: 10.1084/jem.20160833. PubMed DOI PMC

Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, et al. Single-Cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019;50(253–271):e256. doi: 10.1016/j.immuni.2018.11.004. PubMed DOI PMC

Hayashi T, Shimonaka S, Elahi M, Matsumoto SE, Ishiguro K, Takanashi M, Hattori N, Motoi Y. Learning deficits accompanied by microglial proliferation after the long-term post-injection of Alzheimer's disease brain extract in mouse brains. J Alzheimers Dis. 2021;79:1701–1711. doi: 10.3233/JAD-201002. PubMed DOI

He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, Zhang B, Gathagan RJ, Yue C, Dengler C, et al. Amyloid-beta plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018;24:29–38. doi: 10.1038/nm.4443. PubMed DOI PMC

He Z, McBride JD, Xu H, Changolkar L, Kim SJ, Zhang B, Narasimhan S, Gibbons GS, Guo JL, Kozak M, et al. Transmission of tauopathy strains is independent of their isoform composition. Nat Commun. 2020;11:7. doi: 10.1038/s41467-019-13787-x. PubMed DOI PMC

Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014;111:E4376–4385. doi: 10.1073/pnas.1411649111. PubMed DOI PMC

Hopp SC, Lin Y, Oakley D, Roe AD, DeVos SL, Hanlon D, Hyman BT. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer's disease. J Neuroinflammation. 2018;15:269. doi: 10.1186/s12974-018-1309-z. PubMed DOI PMC

Hu W, Zhang X, Tung YC, Xie S, Liu F, Iqbal K. Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 2016;12:1066–1077. doi: 10.1016/j.jalz.2016.01.014. PubMed DOI

Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013;33:1024–1037. doi: 10.1523/JNEUROSCI.2642-12.2013. PubMed DOI PMC

Iba M, McBride JD, Guo JL, Zhang B, Trojanowski JQ, Lee VM. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections. Acta Neuropathol. 2015;130:349–362. doi: 10.1007/s00401-015-1458-4. PubMed DOI PMC

Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, Trojanowski JQ, Lee VM. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron. 1999;24:751–762. doi: 10.1016/s0896-6273(00)81127-7. PubMed DOI

Ishizawa K, Dickson DW. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol. 2001;60:647–657. doi: 10.1093/jnen/60.6.647. PubMed DOI

Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669–673. doi: 10.1038/s41586-019-1769-z. PubMed DOI PMC

Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella CV, Landi A, Szekeres PG, Murray TK, Ahmed Z, et al. Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci. 2016;36:762–772. doi: 10.1523/jneurosci.3542-15.2016. PubMed DOI PMC

Jiang S, Bhaskar K. Degradation and transmission of Tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy. Front Mol Neurosci. 2020;13:586731. doi: 10.3389/fnmol.2020.586731. PubMed DOI PMC

Jin N, Gu J, Wu R, Chu D, Tung YC, Wegiel J, Wisniewski T, Gong CX, Iqbal K, Liu F. Tau seeding activity in various regions of down syndrome brain assessed by two novel assays. Acta Neuropathol Commun. 2022;10:132. doi: 10.1186/s40478-022-01436-2. PubMed DOI PMC

Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol. 2011;70:532–540. doi: 10.1002/ana.22615. PubMed DOI PMC

Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C. Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA. 1999;96:9409–9414. doi: 10.1073/pnas.96.16.9409. PubMed DOI PMC

Kambe T, Motoi Y, Inoue R, Kojima N, Tada N, Kimura T, Sahara N, Yamashita S, Mizoroki T, Takashima A, et al. Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice. Neurobiol Dis. 2011;42:404–414. doi: 10.1016/j.nbd.2011.02.002. PubMed DOI

Kazim SF, Sharma A, Saroja SR, Seo JH, Larson CS, Ramakrishnan A, Wang M, Blitzer RD, Shen L, Pena CJ, et al. Chronic intermittent hypoxia enhances pathological tau seeding, propagation, and accumulation and exacerbates Alzheimer-like memory and synaptic plasticity deficits and molecular signatures. Biol Psychiatry. 2022;91:346–358. doi: 10.1016/j.biopsych.2021.02.973. PubMed DOI PMC

Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol. 1999;9:663–679. doi: 10.1111/j.1750-3639.1999.tb00549.x. PubMed DOI PMC

Kovacs GG. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol. 2015;41:3–23. doi: 10.1111/nan.12208. PubMed DOI

Kovacs GG, Ghetti B, Goedert M. Classification of diseases with accumulation of Tau protein. Neuropathol Appl Neurobiol. 2022;48:e12792. doi: 10.1111/nan.12792. PubMed DOI PMC

Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB, Coughlin D, Giese A, Grossman M, Kurz C, et al. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 2020;140:99–119. doi: 10.1007/s00401-020-02158-2. PubMed DOI PMC

Kyrargyri V, Vega-Flores G, Gruart A, Delgado-García JM, Probert L. Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice. Glia. 2015;63:549–566. doi: 10.1002/glia.22756. PubMed DOI

Labzin LI, Heneka MT, Latz E. Innate Immunity and Neurodegeneration. Annu Rev Med. 2018;69:437–449. doi: 10.1146/annurev-med-050715-104343. PubMed DOI

Lamkanfi M, Dixit VM. The inflammasome turns 15. Nature. 2017;548:534–535. doi: 10.1038/548534a. PubMed DOI

Lamkanfi M, Dixit VM. A new lead to NLRP3 inhibition. J Exp Med. 2017;214:3147–3149. doi: 10.1084/jem.20171848. PubMed DOI PMC

Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Clos AL, Jackson GR, Kayed R. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener. 2011;6:39. doi: 10.1186/1750-1326-6-39. PubMed DOI PMC

Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T, Neugebauer V, Jackson GR, Kayed R. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep. 2012;2:700. doi: 10.1038/srep00700. PubMed DOI PMC

Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005;120:701–713. doi: 10.1016/j.cell.2005.01.015. PubMed DOI

Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: a systematic review and meta-analysis. JAMA Neurol. 2017;74:1237–1245. doi: 10.1001/jamaneurol.2017.2180. PubMed DOI PMC

Leroux E, Perbet R, Caillierez R, Richetin K, Lieger S, Espourteille J, Bouillet T, Begard S, Danis C, Loyens A, et al. Extracellular vesicles: major actors of heterogeneity in tau spreading among human tauopathies. Mol Ther. 2022;30:782–797. doi: 10.1016/j.ymthe.2021.09.020. PubMed DOI PMC

Levarska L, Zilka N, Jadhav S, Neradil P, Novak M. Of rodents and men: the mysterious interneuronal pilgrimage of misfolded protein tau in Alzheimer's disease. J Alzheimers Dis. 2013;37:569–577. doi: 10.3233/JAD-131106. PubMed DOI

Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12:50. doi: 10.1186/s13024-017-0192-x. PubMed DOI PMC

Li L, Shi R, Gu J, Tung YC, Zhou Y, Zhou D, Wu R, Chu D, Jin N, Deng K, et al. Alzheimer's disease brain contains tau fractions with differential prion-like activities. Acta Neuropathol Commun. 2021;9:28. doi: 10.1186/s40478-021-01127-4. PubMed DOI PMC

Lodder C, Scheyltjens I, Stancu IC, Botella Lucena P, Gutierrez de Rave M, Vanherle S, Vanmierlo T, Cremers N, Vanrusselt H, Brone B, et al. CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia. Acta Neuropathol Commun. 2021;9:108. doi: 10.1186/s40478-021-01204-8. PubMed DOI PMC

Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161. doi: 10.1038/srep11161. PubMed DOI PMC

Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020;23:194–208. doi: 10.1038/s41593-019-0566-1. PubMed DOI PMC

Mate De Gerando A, Welikovitch LA, Khasnavis A, Commins C, Glynn C, Chun JE, Perbet R, Hyman BT. Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau. Acta Neuropathol. 2023;146:191–210. doi: 10.1007/s00401-023-02600-1. PubMed DOI PMC

Mate V, Smolek T, Kazmerova ZV, Jadhav S, Brezovakova V, Jurkanin B, Uhrinova I, Basheer N, Zilka N, Katina S, et al. Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy. Front Aging Neurosci. 2022;14:935973. doi: 10.3389/fnagi.2022.935973. PubMed DOI PMC

Meisl G, Hidari E, Allinson K, Rittman T, DeVos SL, Sanchez JS, Xu CK, Duff KE, Johnson KA, Rowe JB, et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Sci Adv. 2021;7:eabh1448. doi: 10.1126/sciadv.abh1448. PubMed DOI PMC

Miao J, Shi R, Li L, Chen F, Zhou Y, Tung YC, Hu W, Gong CX, Iqbal K, Liu F. Pathological Tau from Alzheimer's brain induces site-specific hyperphosphorylation and SDS- and reducing agent-resistant aggregation of Tau in vivo. Front Aging Neurosci. 2019;11:34. doi: 10.3389/fnagi.2019.00034. PubMed DOI PMC

Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J Biol Chem. 2015;290:14893–14903. doi: 10.1074/jbc.M115.652693. PubMed DOI PMC

Moloney CM, Lowe VJ, Murray ME. Visualization of neurofibrillary tangle maturity in Alzheimer's disease: a clinicopathologic perspective for biomarker research. Alzheimers Dement. 2021;17:1554–1574. doi: 10.1002/alz.12321. PubMed DOI PMC

Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Alavi Naini SM, Mandelkow EM, Mandelkow E, Buee L, Goedert M, et al. What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun. 2017;5:99. doi: 10.1186/s40478-017-0488-7. PubMed DOI PMC

Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011;10:785–796. doi: 10.1016/S1474-4422(11)70156-9. PubMed DOI PMC

Murray ME, Kouri N, Lin WL, Jack CR, Jr, Dickson DW, Vemuri P. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias. Alzheimers Res Ther. 2014;6:1. doi: 10.1186/alzrt231. PubMed DOI PMC

Narasimhan S, Changolkar L, Riddle DM, Kats A, Stieber A, Weitzman SA, Zhang B, Li Z, Roberson ED, Trojanowski JQ, et al. Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J Exp Med. 2020 doi: 10.1084/jem.20190783. PubMed DOI PMC

Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV, He Z, Zhang B, Gathagan RJ, Trojanowski JQ, et al. Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci. 2017;37:11406–11423. doi: 10.1523/JNEUROSCI.1230-17.2017. PubMed DOI PMC

Narasimhan S, Lee VMY. The use of mouse models to study cell-to-cell transmission of pathological tau. Methods Cell Biol. 2017;141:287–305. doi: 10.1016/bs.mcb.2017.06.009. PubMed DOI PMC

Neidl R, Schneider A, Bousiges O, Majchrzak M, Barbelivien A, de Vasconcelos AP, Dorgans K. Late-life environmental enrichment induces acetylation events and nuclear factor κB-dependent regulations in the hippocampus of aged rats showing improved plasticity and learning. J Neurosci. 2016;36(4351):4361. doi: 10.1523/jneurosci.3239-15.2016. PubMed DOI PMC

Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–381. doi: 10.1097/NEN.0b013e31825018f7. PubMed DOI PMC

Nies SH, Takahashi H, Herber CS, Huttner A, Chase A, Strittmatter SM. Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-beta. J Biol Chem. 2021;297:101159. doi: 10.1016/j.jbc.2021.101159. PubMed DOI PMC

O'Mahony A, Raber J, Montano M, Foehr E, Han V, Lu SM, Kwon H, LeFevour A, Chakraborty-Sett S, Greene WC. NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity. Mol Cell Biol. 2006;26:7283–7298. doi: 10.1128/mcb.00510-06. PubMed DOI PMC

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–421. doi: 10.1016/s0896-6273(03)00434-3. PubMed DOI

Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E, et al. Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol Dis. 2015;73:83–95. doi: 10.1016/j.nbd.2014.08.032. PubMed DOI PMC

Perez-Nievas BG, Stein TD, Tai HC, Dols-Icardo O, Scotton TC, Barroeta-Espar I, Fernandez-Carballo L, de Munain EL, Perez J, Marquie M, et al. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain. 2013;136:2510–2526. doi: 10.1093/brain/awt171. PubMed DOI PMC

Polanco JC, Li C, Durisic N, Sullivan R, Gotz J. Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun. 2018;6:10. doi: 10.1186/s40478-018-0514-4. PubMed DOI PMC

Probst A, Gotz J, Wiederhold KH, Tolnay M, Mistl C, Jaton AL, Hong M, Ishihara T, Lee VM, Trojanowski JQ, et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 2000;99:469–481. doi: 10.1007/s004010051148. PubMed DOI

Ramirez DMO, Whitesell JD, Bhagwat N, Thomas TL, Ajay AD, Nawaby A, Delatour B, Bay S, LaFaye P, Knox JE, et al. Endogenous pathology in tauopathy mice progresses via brain networks. bioRxiv. 2023 doi: 10.1101/2023.05.23.541792. PubMed DOI PMC

Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L) J Neurosci. 2005;25:10637–10647. doi: 10.1523/JNEUROSCI.3279-05.2005. PubMed DOI PMC

Roberts M, Sevastou I, Imaizumi Y, Mistry K, Talma S, Dey M, Gartlon J, Ochiai H, Zhou Z, Akasofu S, et al. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2020;8:13. doi: 10.1186/s40478-020-0884-2. PubMed DOI PMC

Rosenberg A, Mangialasche F, Ngandu T, Solomon A, Kivipelto M. Multidomain interventions to prevent cognitive impairment, Alzheimer's disease, and dementia: from FINGER to world-wide FINGERS. J Prevent Alzheimer's Dis. 2020;7:29–36. doi: 10.14283/jpad.2019.41. PubMed DOI PMC

Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N, Takamatsu-Yukawa K, Hu J, Wang Y, Hersh S, et al. Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021;144:288–309. doi: 10.1093/brain/awaa376. PubMed DOI PMC

Samudra N, Lane-Donovan C, VandeVrede L, Boxer AL. Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues. J Clin Invest. 2023 doi: 10.1172/JCI168553. PubMed DOI PMC

Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–1288. doi: 10.1016/j.neuron.2014.04.047. PubMed DOI PMC

Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309:476–481. doi: 10.1126/science.1113694. PubMed DOI PMC

Saranza GM, Whitwell JL, Kovacs GG, Lang AE. Corticobasal degeneration. Int Rev Neurobiol. 2019;149:87–136. doi: 10.1016/bs.irn.2019.10.014. PubMed DOI

Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer's disease. Lancet (London, England) 2021;397:1577–1590. doi: 10.1016/s0140-6736(20)32205-4. PubMed DOI PMC

Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A, Kametani F, Garringer HJ, et al. Structure-based classification of tauopathies. Nature. 2021;598:359–363. doi: 10.1038/s41586-021-03911-7. PubMed DOI PMC

Skachokova Z, Martinisi A, Flach M, Sprenger F, Naegelin Y, Steiner-Monard V, Sollberger M, Monsch AU, Goedert M, Tolnay M, et al. Cerebrospinal fluid from Alzheimer's disease patients promotes tau aggregation in transgenic mice. Acta Neuropathol Commun. 2019;7:72. doi: 10.1186/s40478-019-0725-3. PubMed DOI PMC

Smolek T, Cubinkova V, Brezovakova V, Valachova B, Szalay P, Zilka N, Jadhav S. Genetic background influences the propagation of tau pathology in transgenic rodent models of tauopathy. Front Aging Neurosci. 2019;11:343. doi: 10.3389/fnagi.2019.00343. PubMed DOI PMC

Smolek T, Jadhav S, Brezovakova V, Cubinkova V, Valachova B, Novak P, Zilka N. First-in-rat study of human alzheimer's disease tau propagation. Mol Neurobiol. 2019;56:621–631. doi: 10.1007/s12035-018-1102-0. PubMed DOI

Snow WM, Albensi BC. Neuronal gene targets of NF-κB and their dysregulation in alzheimer's disease. Front Mol Neurosci. 2016;9:118. doi: 10.3389/fnmol.2016.00118. PubMed DOI PMC

Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brone B, Huaux F, Octave JN, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617. doi: 10.1007/s00401-018-01957-y. PubMed DOI PMC

Stancu IC, Lodder C, Botella Lucena P, Vanherle S, Gutierrez de Rave M, Terwel D, Bottelbergs A, Dewachter I. The NLRP3 inflammasome modulates tau pathology and neurodegeneration in a tauopathy model. Glia. 2022;70:1117–1132. doi: 10.1002/glia.24160. PubMed DOI PMC

Stancu IC, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E, Buist A, Terwel D, Baatsen P, Oyelami T, et al. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol. 2015;129:875–894. doi: 10.1007/s00401-015-1413-4. PubMed DOI PMC

Streit WJ, Xue Q-S, Tischer J, Bechmann I. Microglial pathology. Acta Neuropathol Commun. 2014;2:142. doi: 10.1186/s40478-014-0142-6. PubMed DOI PMC

Takeda S, Wegmann S, Cho H, DeVos SL, Commins C, Roe AD, Nicholls SB, Carlson GA, Pitstick R, Nobuhara CK, et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain. Nat Commun. 2015;6:8490. doi: 10.1038/ncomms9490. PubMed DOI PMC

Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y, Arima K, Yoshida M, et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 2016;131:267–280. doi: 10.1007/s00401-015-1503-3. PubMed DOI PMC

Terai K, Matsuo A, McGeer PL. Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res. 1996;735:159–168. doi: 10.1016/0006-8993(96)00310-1. PubMed DOI

Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem. 2005;280:3963–3973. doi: 10.1074/jbc.M409876200. PubMed DOI

Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–1800. doi: 10.1212/wnl.58.12.1791. PubMed DOI

Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, Servaes S, Benedet AL, Ashton NJ, Karikari TK, et al. Biomarker modeling of Alzheimer’s disease using PET-based Braak staging. Nature Aging. 2022;2:526–535. doi: 10.1038/s43587-022-00204-0. PubMed DOI PMC

Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, Servaes S, Benedet AL, Ashton NJ, Karikari TK, et al. Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging. 2022;2:526–535. doi: 10.1038/s43587-022-00204-0. PubMed DOI PMC

Van Kolen K, Malia TJ, Theunis C, Nanjunda R, Teplyakov A, Ernst R, Wu SJ, Luo J, Borgers M, Vandermeeren M, et al. Discovery and functional characterization of hPT3, a humanized anti-phospho tau selective monoclonal antibody. J Alzheimers Dis. 2020;77:1397–1416. doi: 10.3233/JAD-200544. PubMed DOI

Vaquer-Alicea J, Diamond MI, Joachimiak LA. Tau strains shape disease. Acta Neuropathol. 2021;142:57–71. doi: 10.1007/s00401-021-02301-7. PubMed DOI PMC

Vasconcelos B, Stancu IC, Buist A, Bird M, Wang P, Vanoosthuyse A, Van Kolen K, Verheyen A, Kienlen-Campard P, Octave JN, et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 2016;131:549–569. doi: 10.1007/s00401-015-1525-x. PubMed DOI PMC

Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V, Boom A, Mansour S, Leroy K, Ando K, et al. Amyloid-beta pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol. 2019;137:397–412. doi: 10.1007/s00401-018-1953-5. PubMed DOI

Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V, Boom A, Mansour S, Leroy K, Ando K, et al. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol. 2019;137:397–412. doi: 10.1007/s00401-018-1953-5. PubMed DOI

Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13:1969. doi: 10.1038/s41467-022-29552-6. PubMed DOI PMC

Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, et al. Microglial NF-kappaB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13:1969. doi: 10.1038/s41467-022-29552-6. PubMed DOI PMC

Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K, Chandupatla R, Maetzler W, Schneider A, Mandelkow E, et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener. 2017;12:5. doi: 10.1186/s13024-016-0143-y. PubMed DOI PMC

Weitzman SA, Narasimhan S, He Z, Changolkar L, McBride JD, Zhang B, Schellenberg GD, Trojanowski JQ, Lee VMY. Insoluble tau from human FTDP-17 cases exhibit unique transmission properties in vivo. J Neuropathol Exp Neurol. 2020;79:941–949. doi: 10.1093/jnen/nlaa086. PubMed DOI PMC

Williams T, Ruiz AJ, Ruiz AM, Vo Q, Tsering W, Xu G, McFarland K, Giasson BI, Sullivan P, Borchelt DR, et al. Impact of APOE genotype on prion-type propagation of tauopathy. Acta Neuropathol Commun. 2022;10:57. doi: 10.1186/s40478-022-01359-y. PubMed DOI PMC

Winston CN, Aulston B, Rockenstein EM, Adame A, Prikhodko O, Dave KN, Mishra P, Rissman RA, Yuan SH. Neuronal exosome-derived human tau is toxic to recipient mouse neurons in vivo. J Alzheimers Dis. 2019;67:541–553. doi: 10.3233/JAD-180776. PubMed DOI PMC

Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, Steinberg JI, Margittai M, Kayed R, Zurzolo C, et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem. 2013;288:1856–1870. doi: 10.1074/jbc.M112.394528. PubMed DOI PMC

Wu R, Gu J, Zhou D, Tung YC, Jin N, Chu D, Hu W, Wegiel J, Gong CX, Iqbal K, et al. Seeding-competent tau in gray matter versus white matter of alzheimer's disease brain. J Alzheimers Dis. 2021;79:1647–1659. doi: 10.3233/JAD-201290. PubMed DOI

Xu H, O'Reilly M, Gibbons GS, Changolkar L, McBride JD, Riddle DM, Zhang B, Stieber A, Nirschl J, Kim SJ, et al. In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics. Acta Neuropathol. 2021;141:193–215. doi: 10.1007/s00401-020-02253-4. PubMed DOI PMC

Xu Y, Propson NE, Du S, Xiong W, Zheng H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc Natl Acad Sci USA. 2021 doi: 10.1073/pnas.2023418118. PubMed DOI PMC

Xu Y, Propson NE, Du S, Xiong W, Zheng H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc Natl Acad Sci. 2021;118:e2023418118. doi: 10.1073/pnas.2023418118. PubMed DOI PMC

Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011;306:613–619. doi: 10.1001/jama.2011.1115. PubMed DOI PMC

Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–351. doi: 10.1016/j.neuron.2007.01.010. PubMed DOI

Zareba-Paslawska J, Patra K, Kluzer L, Revesz T, Svenningsson P. Tau isoform-driven CBD pathology transmission in oligodendrocytes in humanized tau mice. Front Neurol. 2020;11:589471. doi: 10.3389/fneur.2020.589471. PubMed DOI PMC

Zhang F, Zhong R, Li S, Fu Z, Cheng C, Cai H, Le W. Acute hypoxia induced an imbalanced M1/M2 activation of microglia through NF-kappaB signaling in alzheimer's disease mice and wild-type littermates. Front Aging Neurosci. 2017;9:282. doi: 10.3389/fnagi.2017.00282. PubMed DOI PMC

Zhang G, Meng L, Wang Z, Peng Q, Chen G, Xiong J, Zhang Z. Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer's disease. Mol Neurodegener. 2022;17:12. doi: 10.1186/s13024-022-00518-y. PubMed DOI PMC

Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell. 2017;168:37–57. doi: 10.1016/j.cell.2016.12.012. PubMed DOI PMC

Zhang W, Falcon B, Murzin AG, Fan J, Crowther RA, Goedert M, Scheres SH. Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer's and Pick's diseases. Elife. 2019 doi: 10.7554/eLife.43584. PubMed DOI PMC

Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, Vidal R, Garringer HJ, Shi Y, Ikeuchi T, et al. Novel tau filament fold in corticobasal degeneration. Nature. 2020;580:283–287. doi: 10.1038/s41586-020-2043-0. PubMed DOI PMC

Zhang W, Xu C, Sun J, Shen HM, Wang J, Yang C. Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: pathogenic mechanisms and therapeutic potential. Acta Pharm Sin B. 2022;12:1019–1040. doi: 10.1016/j.apsb.2022.01.008. PubMed DOI PMC

Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006;580:3582–3588. doi: 10.1016/j.febslet.2006.05.029. PubMed DOI

Zilka N, Kazmerova Z, Jadhav S, Neradil P, Madari A, Obetkova D, Bugos O, Novak M. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J Neuroinflammation. 2012;9:47. doi: 10.1186/1742-2094-9-47. PubMed DOI PMC