Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer's disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term "amyloid" refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer's disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital 100 00 Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady 100 00 Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer Hospital 100 00 Prague Czech Republic

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Salardini A. An Overview of Primary Dementias as Clinicopathological Entities. Semin. Neurol. 2019;39:153–166. doi: 10.1055/s-0039-1683445. PubMed DOI

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

Dickson D.W., Kouri N., Murray M.E., Josephs K.A. Neuropathology of frontotemporal lobar degeneration-Tau (FTLD-Tau) J. Mol. Neurosci. 2011;45:384–389. doi: 10.1007/s12031-011-9589-0. PubMed DOI PMC

MacKenzie I.R., Neumann M. Molecular neuropathology of frontotemporal dementia: Insights into disease mechanisms from postmortem studies. J. Neurochem. 2016;138:54–70. doi: 10.1111/jnc.13588. PubMed DOI

Jellinger K.A. Neuropathology of Dementia Disorders. J. Alzheimers Dis. Parkinsonism. 2014;4:135. doi: 10.4172/2161-0460.1000135. DOI

Chornenka K., Hirsch-Reinshagen V., Perez-Rosendahl M., Feldman H., Segal-Gidan F., Vinters H.V., MacKenzie I.R. Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS) J. Neuropathol. Exp. Neurol. 2020;79:809–812. doi: 10.1093/jnen/nlaa045. PubMed DOI

Thal D.R., Fändrich M. Protein aggregation in Alzheimer’s disease: Aβ and τ and their potential roles in the pathogenesis of AD. Acta Neuropathol. 2015;129:163–165. doi: 10.1007/s00401-015-1387-2. PubMed DOI

Kovacs G.G., Budka H. Prion diseases: From protein to cell pathology. Am. J. Pathol. 2008;172:555–565. doi: 10.2353/ajpath.2008.070442. PubMed DOI PMC

Elhaddaoui A., Pigorsch E., Delacourte A., Turrell S. Competition of congo red and thioflavin S binding to amyloid sites in Alzheimer’s diseased tissue. Biospectroscopy. 1995;1:351–356. doi: 10.1002/bspy.350010506. DOI

Schultz C., Del Tredici K. Neuropathology of Alzheimer’s Disease. Alzheimers Disease Curr. Clin. Neurol. 2004:21–31. doi: 10.1007/978-1-59259-661-4_2. DOI

Hebert L.E., Weuve J., Scherr P.A., Evans D.A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 Census. Neurology. 2013;80:1778–1783. doi: 10.1212/WNL.0b013e31828726f5. PubMed DOI PMC

Montine T.J., Phelps C.H., Beach T.G., Bigio E.H., Cairns N.J., Dickson D.W., Duyckaerts C., Frosch M.P., Masliah E., Mirra S.S., et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol. 2012;123:1–11. doi: 10.1007/s00401-011-0910-3. PubMed DOI PMC

Hyman B.T., Phelps C.H., Beach T.G., Bigio E.H., Cairns N.J., Carrillo M.C., Dickson D.W., Duyckaerts C., Frosch M.P., Masliah E., et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13. doi: 10.1016/j.jalz.2011.10.007. PubMed DOI PMC

Mirra S.S., Heyman A., McKeel D., Sumi S.M., Crain B.J., Brownlee L.M., Vogel F.S., Hughes J.P., Van Belle G., Berg L., et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 1991;41:479–486. doi: 10.1212/WNL.41.4.479. PubMed DOI

Ugalde C.L., Finkelstein D.I., Lawson V.A., Hill A.F. Pathogenic mechanisms of prion protein, amyloid-β and α-synuclein misfolding: The prion concept and neurotoxicity of protein oligomers. J. Neurochem. 2016;139:162–180. doi: 10.1111/jnc.13772. PubMed DOI

Lesné S., Koh M.T., Kotilinek L., Kayed R., Glabe C.G., Yang A., Gallagher M., Ashe K.H. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–357. doi: 10.1038/nature04533. PubMed DOI

Blessed G., Tomlinson B.E., Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br. J. Psychiatry. 1968;114:797–811. doi: 10.1192/bjp.114.512.797. PubMed DOI

Savonenko A.V., Melnikova T., Won P.C. Alzheimer disease. In: Zigmund M.J., Coyle J.T., Rowland L.P., editors. Neurobiology of Brain Disorders. 1st ed. Academic Press; Cambridge, MA, USA: 2014. pp. 321–338.

O’Brien R.J., Wong P.C. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 2011;34:185–204. doi: 10.1146/annurev-neuro-061010-113613. PubMed DOI PMC

Bush A.I., Multhaup G., Moir R.D., Williamson T.G., Small D.H., Rumble B., Pollwein P., Beyreuther K., Masters C.L. A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer’s disease. J. Biol. Chem. 1993;268:16109–16112. PubMed

Multhaup G., Schlicksupp A., Hesse L., Beher D., Ruppert T., Masters C.L., Beyreuther K. The amyloid precursor protein of Alzheimer’s disease in the reduction of copper(II) to copper(I) Science. 1996;271:1406–1409. doi: 10.1126/science.271.5254.1406. PubMed DOI

Smith-Swintosky V.L., Pettigrew L.C., Craddock S.D., Culwell A.R., Rydel R.E., Mattson M.P. Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J. Neurochem. 1994;63:781–784. doi: 10.1046/j.1471-4159.1994.63020781.x. PubMed DOI

Chow V.W., Mattson M.P., Wong P.C., Gleichmann M. An overview of APP processing enzymes and products. Neuro Mol. Med. 2010;12:1–12. doi: 10.1007/s12017-009-8104-z. PubMed DOI PMC

Knowles T.P.J., Vendruscolo M., Dobson C.M. The amyloid state and its association with protein misfolding diseases. Nat. Rev. Mol. Cell Biol. 2014;15:384–396. doi: 10.1038/nrm3810. PubMed DOI

Plant L.D., Boyle J.P., Smith I.F., Peers C., Pearson H.A. The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J. Neurosci. 2003;23:5531–5535. doi: 10.1523/JNEUROSCI.23-13-05531.2003. PubMed DOI PMC

Gravina S.A., Ho L., Eckman C.B., Long K.E., Otvos L., Younkin L.H., Suzuki N., Younkin S.G. Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43) J. Biol. Chem. 1995;270:7013–7016. doi: 10.1074/jbc.270.13.7013. PubMed DOI

Miller D., Papayannopoulos I., Styles J., Bobin S., Lin Y., Biemann K., Iqbal K. Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch. Biochem. Biophys. 1993;301:41–52. doi: 10.1006/abbi.1993.1112. PubMed DOI

Roher A.E., Lowenson J.D., Clarke S., Wolkow C., Wang R.O.N.G., Cotter R.J., Reardon I.M., Zürcher-Neely H.A., Heinrikson R.L., Ball M.J. Structural alterations in the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J. Biol. Chem. 1993;268:3072–3073. PubMed

Vonsattel J.P.G., Myers R.H., Hedley-Whyte E.T., Ropper A.H., Bird E.D., Richardson E.P. Cerebral amyloid angiopathy without and with cerebral hemorrhages: A comparative histological study. Ann. Neurol. 1991;30:637–649. doi: 10.1002/ana.410300503. PubMed DOI

Bernstein S.L., Dupuis N.F., Lazo N.D., Wyttenbach T., Condron M.M., Bitan G., Teplow D.B., Shea J.-E., Ruotolo B.T., Robinson C.V., et al. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat. Chem. 2009;1:326–331. doi: 10.1038/nchem.247. PubMed DOI PMC

Gunther E.C., Strittmatter S.M. Beta-amyloid oligomers and cellular prion protein in Alzheimer’s disease. J. Mol. Med. 2009;88:331–338. doi: 10.1007/s00109-009-0568-7. PubMed DOI PMC

Haass C., Selkoe D.J. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nat. Rev. Mol. Cell Biol. 2007;8:101–112. doi: 10.1038/nrm2101. PubMed DOI

Walsh D.M., Klyubin I., Fadeeva J.V., Cullen W.K., Anwyl R., Wolfe M.S., Rowan M.J., Selkoe D.J. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–539. doi: 10.1038/416535a. PubMed DOI

Hardy J.A., Higgins G.A. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 1992;256:184–185. doi: 10.1126/science.1566067. PubMed DOI

Zhang S., Zhang M., Cai F., Song W. Biological function of Presenilin and its role in AD pathogenesis. Transl. Neurodegener. 2013;2:15. doi: 10.1186/2047-9158-2-15. PubMed DOI PMC

Pimplikar S.W. Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int. J. Biochem. Cell Biol. 2009;41:1261–1268. doi: 10.1016/j.biocel.2008.12.015. PubMed DOI PMC

Leverenz J., Raskind M.A. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: A regional quantitative analysis. Exp. Neurol. 1998;150:296–304. doi: 10.1006/exnr.1997.6777. PubMed DOI

Lemere C.A., Blusztajn J.K., Yamaguchi H., Wisniewski T., Saido T.C., Selkoe D.J. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol. Dis. 1996;3:16–32. doi: 10.1006/nbdi.1996.0003. PubMed DOI

Wiseman F.K., Al-Janabi T., Hardy J., Ferguson-Smith A.C., Nizetic D., Tybulewicz V.L.J., Fisher E.M.C., Strydom A. A genetic cause of Alzheimer disease: Mechanistic insights from Down syndrome. Nat. Rev. Neurosci. 2015;16:564–574. doi: 10.1038/nrn3983. PubMed DOI PMC

Morris G.P., Clark I.A., Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol. Commun. 2014;2:135. doi: 10.1186/s40478-014-0135-5. PubMed DOI PMC

Morris G.P., Clark I., Vissel B. Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease. Acta Neuropathol. 2018;136:663–689. doi: 10.1007/s00401-018-1918-8. PubMed DOI PMC

Clark I.A., Vissel B. Amyloid beta: One of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer’s disease. Br. J. Pharmacol. 2015;172:3714–3727. doi: 10.1111/bph.13181. PubMed DOI PMC

Clark I.A., Vissel B. Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α-synuclein, amyloid-β and insulin resistance in neurodegenerative diseases. Br. J. Pharmacol. 2018;175:3859–3875. doi: 10.1111/bph.14471. PubMed DOI PMC

Nelson P.T., Braak H., Markesbery W.R. Neuropathology and cognitive impairment in Alzheimer disease: A complex but coherent relationship. J. Neuropathol. Exp. Neurol. 2009;68:1–14. doi: 10.1097/NEN.0b013e3181919a48. PubMed DOI PMC

Lesné S., Kotilinek L., Ashe K.H. Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience. 2008;151:745–749. doi: 10.1016/j.neuroscience.2007.10.054. PubMed DOI PMC

Serrano-Pozo A., Frosch M.P., Masliah E., Hyman B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2011;1:a006189. doi: 10.1101/cshperspect.a006189. PubMed DOI PMC

Querol-Vilaseca M., Colom-Cadena M., Pegueroles J., Nuñez-Llaves R., Luque-Cabecerans J., Muñoz-Llahuna L., Andilla J., Belbin O., Spires-Jones T., Gelpi E., et al. Nanoscale structure of amyloid-β plaques in Alzheimer’s disease. Sci. Rep. 2019;9:5181. doi: 10.1038/s41598-019-41443-3. PubMed DOI PMC

Chuen-Chung C.R. Advanced Understanding of Neurodegenerative Diseases Hardcover. IntechOpen; London, UK: 2011. p. 54. DOI

Ringman J.M., Network D.I.A., Goate A., Masters C.L., Cairns N.J., Danek A., Graff-Radford N., Ghetti B., Morris J.C. Dominantly Inherited Alzheimer Network. Genetic heterogeneity in Alzheimer disease and implications for treatment strategies. Curr. Neurol. Neurosci. Rep. 2014;14:499. doi: 10.1007/s11910-014-0499-8. PubMed DOI PMC

Cabranes J.A., Anein I., Barros-Loscertales A., Campos S., Canonico V., Fernandez C., Munoz M.C., Antonello R.M., Belloch-Ugarte V., Avila C., et al. In: Alzheimer’s Disease Research Trends. 1st ed. Chan A.P., editor. Nova Science Publishers Inc.; New York, NY, USA: 2008. p. 324.

Masliah E., Terry R.D., Mallory M., Alford M., Hansen L.A. Diffuse plaques do not accentuate synapse loss in Alzheimer’s disease. Am. J. Pathol. 1990;137:1293–1297. PubMed PMC

Allen S.J. In: Neurobiology of Alzheimer’s Disease. 3rd ed. Dawbarn D., editor. Oxford University Press; Oxford, UK: 2007.

Bussière T., Bard F., Barbour R., Grajeda H., Guido T., Khan K., Schenk D., Games D., Seubert P., Buttini M. Morphological Characterization of Thioflavin-S-Positive Amyloid Plaques in Transgenic Alzheimer Mice and Effect of Passive Aβ Immunotherapy on Their Clearance. Am. J. Pathol. 2004;165:987–995. doi: 10.1016/S0002-9440(10)63360-3. PubMed DOI PMC

Probst A., Brunnschweiler H., Lautenschlager C., Ulrich J. A special type of senile plaque, possibly an initial stage. Acta Neuropathol. 1987;74:133–141. doi: 10.1007/BF00692843. PubMed DOI

Tseng B.P., Esler W.P., Clish C.B., Stimson E.R., Ghilardi J.R., Vinters H.V., Mantyh P.W., Lee J.P., Maggio J.E. Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer’s disease amyloid plaques in human brain preparations. Biochemistry. 1999;38:10424–10431. doi: 10.1021/bi990718v. PubMed DOI

Duckett S., De La Torre J.C. Pathology of the Aging Human Nervous System. 2nd ed. Oxford University Press; Oxford, UK: 2001. p. 161.

DeTure M.A., Dickson D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol, Neurodegener. 2019;14:32. doi: 10.1186/s13024-019-0333-5. PubMed DOI PMC

Dickson T.C., Vickers J.C. The morphological phenotype of amyloid-beta deposits and associated neuritic change in Alzheimer’s disease. Neuroscience. 2001;105:99–107. doi: 10.1016/S0306-4522(01)00169-5. PubMed DOI

Itagaki S., McGeer P., Akiyama H., Zhu S., Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 1989;24:173–182. doi: 10.1016/0165-5728(89)90115-X. PubMed DOI

Malek-Ahmadi M., Perez S.E., Chen K., Mufson E.J. Neuritic and diffuse plaque associations with memory in non-cognitively impaired elderly. J. Alzheimers Dis. 2016;53:1641–1652. doi: 10.3233/JAD-160365. PubMed DOI PMC

Knowles R.B., Wyart C., Buldyrev S.V., Cruz L., Urbanc B., Hasselmo M.E., Stanley H.E., Hyman B.T. Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 1999;96:5274–5279. doi: 10.1073/pnas.96.9.5274. PubMed DOI PMC

Seth L.S., Louis D.N., Ellison D.W. Greenfield’s Neuropathology. 8th ed. Hodder Education Publishers; London, UK: 2008. p. 2400.

Perry A., Brat D. Practical Surgical Neuropathology: A Diagnostic Approach. 2nd ed. Elsevier Health Sciences; Philadelphia, PA, USA: 2017. p. 752.

Baumann B., Woehrer A., Ricken G., Augustin M., Mitter C., Pircher M., Kovacs G.G., Hitzenberger C.K. Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy. Sci. Rep. 2017;7:43477. doi: 10.1038/srep43477. PubMed DOI PMC

Perl D.P. Neuropathology of Alzheimer’s disease. Mt. Sinai J. Med. 2010;77:32–42. doi: 10.1002/msj.20157. PubMed DOI PMC

Thal D.R., Capetillo-Zarate E., Del Tredici K., Braak H. The development of amyloid beta protein deposits in the aged brain. Sci. Aging Knowl. Environ. 2006;2006:re1. doi: 10.1126/sageke.2006.6.re1. PubMed DOI

Yasuhara O., Kawamata T., Aimi Y., McGeer E.G., McGeer P.L. Two types of dystrophic neurites in senile plaques of Alzheimer disease and elderly non-demented cases. Neurosci. Lett. 1994;171:73–76. doi: 10.1016/0304-3940(94)90608-4. PubMed DOI

Valyi-Nagy T. In: Dementias in Neuropathology: A Reference Text of CNS Pathology. 3rd ed. Ellison D., Love S., Chimelli L.M.C., Harding B., Lowe J., Vinters H.V., editors. Elsevier Publishing; Philadephia, PA, USA: 2012. pp. 614–617.

Jankovska N., Olejar T., Kukal J., Matej R. Different Morphology of Neuritic Plaques in the Archicortex of Alzheimer Disease with Comorbid Synucleinopathy: A Pilot Study. Curr. Alzheimer Res. 2020 doi: 10.2174/1875692117999201215162043. Epub ahead of print. PubMed DOI

Armstrong R. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer’s disease. Stage of PublicationFolia Neuro Pathol. 2009;47:289–299. PubMed

Yamaguchi H., Ishiguro K., Sugihara S., Nakazato Y., Kawarabayashi T., Sun X.Y. Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer β-amyloid deposition. Acta Neuropathol. 1994;88:413–419. doi: 10.1007/BF00389492. PubMed DOI

Eikelenboom P., Zhan S.-S., Van Gool W.A., Allsop D. Inflammatory mechanisms in Alzheimer’s disease. Trends Pharmacol. Sci. 1994;15:447–450. doi: 10.1016/0165-6147(94)90057-4. PubMed DOI

Loeffler D.A., Camp D.M., Bennett D.A. Plaque complement activation and cognitive loss in Alzheimer’s disease. J. Neuro Inflamm. 2008;5:9. doi: 10.1186/1742-2094-5-9. PubMed DOI PMC

Verga L., Frangione B., Tagliavini F., Giaccone G., Migheli A., Bugiani O. Alzheimer’s and Down’s patients: Cerebral preamyloid deposits differ ultrastructurally and histochemically from the amyloid of senile plaques. Neurosci. Lett. 1989;105:294–299. doi: 10.1016/0304-3940(89)90636-8. PubMed DOI

Snow A.D., Sekiguchi R.T., Nochlin D., Kalaria R.N., Kimata K. Heparan sulfate proteoglycan in diffuse plaques of hippocampus but not of cerebellum in Alzheimer’s disease brain. Am. J. Pathol. 1994;144:337–347. PubMed PMC

Desai P.P., Ikonomovic M.D., Abrahamson E.E., Hamilton R.L., Isanski B.A., Hope C.E., Klunk W.E., DeKosky S.T., Kamboh M.I. Apolipoprotein D is a component of compact but not diffuse amyloid-beta plaques in Alzheimer’s disease temporal cortex. Neurobiol. Dis. 2005;20:574–582. doi: 10.1016/j.nbd.2005.04.012. PubMed DOI

Atwood C.S., Obrenovitch M.E., Liu T., Chan H., Perry G., Smith M.A., Martins R.N. Amyloid-beta: A chameleon walking in two worlds: A review of the trophic and toxic properties of amyloid-β. Brain Res. Rev. 2004;43:1–6. doi: 10.1016/S0165-0173(03)00174-7. PubMed DOI

Mann D.M.A., Younis N., Jones D., Stoddart R.W. The time course of pathological events in Down’s syndrome with particular reference to the involvement of microglial cells and deposits of b/A4. Neurodegeneration. 1992;1:201–215.

Bush A.I., Pettingell W.H., Multhaup G., Paradis M.D., Vonsattel J.P., Gusella J.F., Beyreuther K., Masters C.L., Tanzi R.E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994;265:1464–1467. doi: 10.1126/science.8073293. PubMed DOI

Shalit F., Sredni B., Stern L., Kott E., Huberman M. Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer’s patients. Neurosci. Lett. 1994;174:130–132. doi: 10.1016/0304-3940(94)90003-5. PubMed DOI

Vogt B. Cingulate Neurobiology and Disease. 3rd ed. Oxford University Press; Oxford, UK: 2009.

Bahmanyar S., Higgins G.A., Goldgaber D. Localization of amyloid β protein messenger RNA in brains from patients with Alzheimer’s disease. Science. 1987;237:77–80. doi: 10.1126/science.3299701. PubMed DOI

Armstrong R.A. Diffuse β-amyloid (Aβ) deposits and neurons: In situ secretion or diffusion of Aβ? Alzheimer Rep. 2001;3:289–294.

Armstrong R.A. Laminar distribution of β-amyloid (Aβ) peptide deposits in the frontal lobe in familial and sporadic Alzheimer’s disease. Folia Neuropathol. 2015;53:15–23. doi: 10.5114/fn.2015.49970. PubMed DOI

Imran M., Mahmood S. An overview of human prion diseases. Virol. J. 2011;8:559. doi: 10.1186/1743-422X-8-559. PubMed DOI PMC

Asher D.M., Gregori L. Human transmissible spongiform encephalopathies: Historic view. Handb. Clin. Neurol. 2018;153:1–17. doi: 10.1016/B978-0-444-63945-5.00001-5. PubMed DOI

Voigtländer T., Klöppel S., Birner P., Jarius C., Flicker H., Verghese-Nikolakaki S., Sklaviadis T., Guentchev M., Budka H. Marked increase of neuronal prion protein immunoreactivity in Alzheimer’s disease and human prion diseases. Acta Neuropathol. 2011;101:417–423. doi: 10.1007/s004010100405. PubMed DOI

Kazlauskaite J., Young A., Gardner C.E., MacPherson J.V., Vénien-Bryan C., Pinheiro T.J.T. An unusual soluble β-turn-rich conformation of prion is involved in fibril formation and toxic to neuronal cells. Biochem. Biophys. Res. Commun. 2005;328:292–305. doi: 10.1016/j.bbrc.2004.12.172. PubMed DOI

Chiesa R. The elusive role of the prion protein and the mechanism of toxicity in prion disease. PLoS Pathog. 2015;11:e1004745. doi: 10.1371/journal.ppat.1004745. PubMed DOI PMC

Hörnlimann B., Riesner D., Kretzschmar H.A. Prions in Humans and Animals. 1st ed. De Gruyter Publishing; Boston, MA, USA: 2006. p. 292.

Klatzo I., Gajusek D.C., Zigas V. Evaluation of pathological findings in twelve cases of kuru. In: Van Boagert L., Radermecker J., Hozay J., Lowenthal A., editors. Encephalities. Elsevier; Amsterdam, The Netherlands: 1959. pp. 172–190.

Beck E., Daniel P.M., Asher D.M., Gajdusek D.C., Gibbs C.J. Experimental kuru in the chimpanzee. A neuropathological study. Jr. Brain. 1973;96:441–462. doi: 10.1093/brain/96.3.441. PubMed DOI

Kitamoto T., Tateishi J., Tashima T., Takeshita I., Barry R.A., DeArmond S.J., Prusiner S.B. Amyloid plaques in Creutzfeldt–Jakob disease stain with prion protein antibodies. Ann. Neurol. 1986;20:204–208. doi: 10.1002/ana.410200205. PubMed DOI

Kuwahara C., Takeuchi A.M., Nishimura T., Haraguchi K., Kubosaki A., Matsumoto Y., Saeki K., Matsumoto Y., Yokoyama T., Itohara S., et al. Prions prevent neuronal cell-line death. Nature. 1999;400:225–226. doi: 10.1038/22241. PubMed DOI

Wulf M.-A., Senatore A., Aguzzi A. The biological function of the cellular prion protein: An update. BMC Biol. 2017;15:34. doi: 10.1186/s12915-017-0375-5. PubMed DOI PMC

Chiesa R., Harris D.A. Fishing for prion protein function. PLoS Biol. 2009;7:e75. doi: 10.1371/journal.pbio.1000075. PubMed DOI PMC

Steele A.D., Lindquist S., Aguzzi A. The prion protein knockout mouse: A phenotype under challenge. Prion. 2007;1:83–93. doi: 10.4161/pri.1.2.4346. PubMed DOI PMC

Linden R., Martins V.R., Prado M.A.M., Cammarota M., Izquierdo I., Brentani R.R. Physiology of the prion protein. Physiol. Rev. 2008;88:673–728. doi: 10.1152/physrev.00007.2007. PubMed DOI

McLennan N.F., Brennan P.M., McNeill A., Davies I., Fotheringham A., Rennison K.A., Ritchie D., Brannan F., Head M.W., Ironside J.W., et al. Prion protein accumulation and neuro-protection in hypoxic brain damage. Am. J Pathol. 2004;165:227–235. doi: 10.1016/S0002-9440(10)63291-9. PubMed DOI PMC

Spudich A., Frigg R., Kilic E., Kilic Ü., Oesch B., Raeber A., Bassetti C.L., Hermann D.M. Aggravation of ischemic brain injury by prion protein deficiency: Role of ERK-1/-2 and STAT-1. Neurobiol. Dis. 2005;20:442–449. doi: 10.1016/j.nbd.2005.04.002. PubMed DOI

Freixes M., Puig B., Blanco R., Ferrer I. Clusterin solubility and aggregation in Creutzfeldt–Jakob disease. Acta Neuropathol. 2004;108:295–301. doi: 10.1007/s00401-004-0891-6. PubMed DOI

Lammie A. Cerebral amyloid angiopathy in Alzheimer’s disease and related disorders. In: Verbeel M.M., De Waal R.M.W., Vinters H.W., editors. Brain. Kluwer Academic Publishers; Amsterdam, The Netherlands: 2001. p. 384. DOI

Laurén J., Gimbel D.A., Nygaard H.B., Gilbert J.W., Strittmatter S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009;457:1128–1132. doi: 10.1038/nature07761. PubMed DOI PMC

Resenberger U.K., Harmeier A., Woerner A.C., Goodman J.L., Müller V., Krishnan R., Vabulas R.M., A Kretzschmar H., Lindquist S., Hartl F.U., et al. The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication. EMBO J. 2011;30:2057–2070. doi: 10.1038/emboj.2011.86. PubMed DOI PMC

Vincent B., Sunyach C., Orzechowski H.-D., George-Hyslop P.S., Checler F. p53-Dependent transcriptional control of cellular prion by presenilins. J. Neurosci. 2009;29:6752–6760. doi: 10.1523/JNEUROSCI.0789-09.2009. PubMed DOI PMC

Han B.H., DeMattos R.B., Dugan L.L., Kim-Han J.S., Brendza R.P., Fryer J.D., Kierson M., Cirrito J., Quick K., Harmony J.A.K., et al. Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia. Nat Med. 2001;7:338–343. doi: 10.1038/85487. PubMed DOI

Jones S.E., Jomary C. Clusterin. Int. J. Biochem. Cell Biol. 2002;34:427–431. doi: 10.1016/S1357-2725(01)00155-8. PubMed DOI

McLaughlin L., Zhu G., Mistry M., Ley-Ebert C., Stuart W.D., Florio C.J., Groen P.A., Witt S.A., Kimball T.R., Witte D.P., et al. Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis. J. Clin. Investig. 2000;106:1105–1113. doi: 10.1172/JCI9037. PubMed DOI PMC

Michel D., Chatelain G., North S., Brun G. Stress-induced transcription of the clusterin/apoJ gene. Biochem. J. 1997;328:45–50. doi: 10.1042/bj3280045. PubMed DOI PMC

Yang C.R., Leskov K., Elberlein H., Criswell T., Pink J.J., Kinsella T.J., Boothman D.A. Nuclear clusterin/XIP8, and x-ray-induced Ku70-binding protein that signals cell death. Proc. Natl. Acad. Sci. USA. 2001;97:5907–5912. doi: 10.1073/pnas.97.11.5907. PubMed DOI PMC

Schwochau G.B., Nath K.A., Rosenberg M.E. Clusterin protects against oxidative stress in vitro through aggregative and nonaggregative properties. Kidney Int. 1998;53:1647–1653. doi: 10.1046/j.1523-1755.1998.00902.x. PubMed DOI

Rosenberg M.E., Silkensen J. Clusterin: Physiologic and pathophysiologic considerations. Int. J. Biochem. Cell Biol. 1995;27:633–645. doi: 10.1016/1357-2725(95)00027-M. PubMed DOI

Ishii T., Haga S., Yagishita S., Tateishi J. The presence of complements in amyloid plaques of Creutzfeldt–Jakob disease and Gerstmann–Straussler–Scheinker disease. Appl. Pathol. 1984;2:370–379. PubMed

Graner E., Mercadante A.F., Zanata S.M., Forlenza O.V., Cabral A.L., Veiga S.S., A Juliano M., Roesler R., Walz R., Minetti A., et al. Cellular prion protein binds laminin and mediates neuritogenesis. Mol. Brain Res. 2000;76:85–92. doi: 10.1016/S0169-328X(99)00334-4. PubMed DOI

Gajdusek D., Zigas V. Kuru; clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. Am. J. Med. 1959;26:442–469. doi: 10.1016/0002-9343(59)90251-7. PubMed DOI

Gajdusek D., Zigas V. Studies on kuru. 1. The ethnologic setting of kuru. Am. J. Trop. Med. Hyg. 1961;10:80–91. doi: 10.4269/ajtmh.1961.10.80. PubMed DOI

Liberski P.P., Gajos A., Sikorska B., Lindenbaum S. Kuru, the First Human Prion Disease. Viruses. 2019;11:232. doi: 10.3390/v11030232. PubMed DOI PMC

Beck E., Daniel P.M. Prion diseases from a neuropathologist’s perspective. In: Prusiner S.B., Collinge J., Powell J., Anderton B., editors. Prion Diseases of Humans and Animals. Ellis Horwood; New York, NY, USA: 1993. pp. 63–65.

Hainfellner J.A., Liberski P.P., Guiroy D.C., Cervenáková L., Brown P., Gajdusek D.C., Budka H. Pathology and immunocytochemistry of a kuru brain. Brain Pathol. 1997;7:547–553. doi: 10.1111/j.1750-3639.1997.tb01072.x. PubMed DOI PMC

Piccardo P., Šafář J., Ceroni M., Gajdusek D.C., Gibbs C.J., Jr. Immunohistochemical localization of prion protein in spongiform encephalopathies and normal brain tissue. Neurology. 1990;40:518–522. doi: 10.1212/WNL.40.3_Part_1.518. PubMed DOI

Vacca V.M., Jr. CJD: Understanding Creutzfeldt–Jakob disease. Nursing. 2016;46:36–42. doi: 10.1097/01.NURSE.0000480598.84274.0f. PubMed DOI

Gençer A.G., Pelin Z., Kucukali C.I., Topçuoğlu Ö.B., Yilmaz N. Creutzfeldt–Jakob disease. Psychogeriatrics. 2011;11:119–124. doi: 10.1111/j.1479-8301.2011.00361.x. PubMed DOI

Sikorska B., Knight R., Ironside J.W., Liberski P.P. Creutzfeldt–Jakob disease. Adv. Exp. Med. Biol. 2012;724:76–90. doi: 10.1007/978-1-4614-0653-2_6. PubMed DOI

Budka H., Aguzzi A., Brown P., Brucher J.-M., Bugiani O., Gullotta F., Haltia M., Hauw J.-J., Ironside J.W., Jellinger K., et al. Neuropathological diagnostic criteria for Creutzfeldt–Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases) Brain Pathol. 1995;5:459–466. doi: 10.1111/j.1750-3639.1995.tb00625.x. PubMed DOI

Bell J.E., Ironside J.W. Neuropathology of spongiform encephalopathies in humans. Br. Med. Bull. 1993;49:738–777. doi: 10.1093/oxfordjournals.bmb.a072645. PubMed DOI

Collinge J. Variant Creutzfeldt–Jakob disease. Lancet. 1999;354:317–323. doi: 10.1016/S0140-6736(99)05128-4. PubMed DOI

Hill A.F., Joiner S., Wadsworth J.D.F., Sidle K.C.L., Bell J.E., Budka H., Ironside J.W., Collinge J. Molecular classification of sporadic Creutzfeldt–Jakob disease. Brain. 2003;126:1333–1346. doi: 10.1093/brain/awg125. PubMed DOI

Brown P., Cathala F., Raubertas R.F., Gajdusek D.C., Castaigne P. The epidemiology of Creutzfeldt–Jakob disease: Conclusion of a 15-year investigation in France and review of the world literature. Neurology. 1987;37:895–904. doi: 10.1212/WNL.37.6.895. PubMed DOI

Gao L.-P., Shi Q., Xiao K., Wang J., Zhou W., Chen C., Dong X. The genetic Creutzfeldt–Jakob disease with E200K mutation: Analysis of clinical, genetic and laboratory features of 30 Chinese patients. Sci. Rep. 2019;9:1836. doi: 10.1038/s41598-019-38520-y. PubMed DOI PMC

Will R.G. Acquired prion disease: Iatrogenic CJD, variant CJD, kuru. Br. Med Bull. 2003;66:255–265. doi: 10.1093/bmb/66.1.255. PubMed DOI

Lantos P. From slow virus to prion: A review of transmissible spongiform encephalopathies. Histopathology. 1992;20:1–11. doi: 10.1111/j.1365-2559.1992.tb00909.x. PubMed DOI

Duyckaerts C., Dickson D.W. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. 2nd ed. Wiley-Blackwell; Hoboken, NJ, USA: 2011. pp. 68–71.

Vickers J.C., Mitew S., Woodhouse A., Fernandez-Martos C.M., Kirkcaldie M.T., Canty A.J., McCormack G.H., King A.E. Defining the Earliest Pathological Changes of Alzheimer’s Disease. Curr. Alzheimer Res. 2016;13:281–287. doi: 10.2174/1567205013666151218150322. PubMed DOI PMC

D’Amore J.D., Kajdasz S.T., McLellan M.E., Bacskai B.J., Stern E.A., Hyman B.T. In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J. Neuropathol. Exp. Neurol. 2003;62:137–145. doi: 10.1093/jnen/62.2.137. PubMed DOI

Parchi P., Giese A., Capellari S., Brown P., Schulz-Schaeffer W., Windl O., Zerr I., Budka H., Kopp N., Piccardo P., et al. Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 1999;46:224–233. doi: 10.1002/1531-8249(199908)46:2<224::AID-ANA12>3.0.CO;2-W. PubMed DOI

Rossi M., Saverioni D., Di Bari M.A., Baiardi S., Lemstra A.W., Pirisinu L., Capellari S., Rozemuller A., Nonno R., Parchi P. Atypical Creutzfeldt–Jakob disease with PrP-amyloid plaques in white matter: Molecular characterization and transmission to bank voles show the M1 strain signature. Acta Neuropathol. Commun. 2017;5:87. doi: 10.1186/s40478-017-0496-7. PubMed DOI PMC

Tatzelt J. Prion Proteins. Springer; Berlin\Heidelberg, Germany: 2011. p. 29.

The Neuropathology of CJD. [(accessed on 13 November 2020)]; Available online: https://www.cjd.ed.ac.uk/sites/default/files/neuropath.pdf.

Nair A.K., Sabbagh M.N. Geriatric Neurology. 1st ed. Wiley-Blackwell; Hoboken, NJ, USA: 2014. p. 277.

Brown D. Neurodegeneration and Prion Disease. Springer; New York, NY, USA: 2005. p. 33.

Sobel R.A. Greenfield’s Neuropathology, Ninth Edition; 2-Volume Set. J. Neuropathol. Exp. Neurol. 2015;74:1185. doi: 10.1093/jnen/74.12.1185. DOI

Kobayashi A., Arima K., Ogawa M., Murata M., Fukuda T., Kitamoto T. Plaque-type deposition of prion protein in the damaged white matter of sporadic Creutzfeldt–Jakob disease MM1 patients. Acta Neuropathol. 2008;116:561–566. doi: 10.1007/s00401-008-0425-8. PubMed DOI

Liberski P.P. Gerstmann–Sträussler–Scheinker Disease. In: Ahmad S.I., editor. Neurodegenerative Diseases. Advances in Experimental Medicine and Biology. Springer; New York, NY, USA: 2012. [(accessed on 20 October 2020)]. Available online: PubMed DOI

Gambetti P., Kong Q., Zou W., Parchi P., Chen S.G. Sporadic and familial CJD: Classification and characterisation. Br. Med. Bull. 2003;66:213–239. doi: 10.1093/bmb/66.1.213. PubMed DOI

Ghetti B., Tagliavini F., Takao M., Bugiani O., Piccardo P. Hereditary prion protein amyloidoses. Clin. Lab. Med. 2003;23:65–85. doi: 10.1016/S0272-2712(02)00064-1. PubMed DOI

Galatioto S., Ruggeri D., Gullotta F. Gerstmann–Sträussler–Scheinker syndrome in a Sicilian patient. Neuropathological aspects. Pathologica. 1995;87:659–665. PubMed

Campbell T.A., Palmer M.S., Will R.G., Gibb W., Luthert P.J., Collinge J. A prion disease with a novel 96-base pair insertional mutation in the prion protein gene. Neurology. 1996;46:761–766. doi: 10.1212/WNL.46.3.761. PubMed DOI

Cochran E.J., Bennett D.A., Cervenakova L., Kenney K., Bernard B., Foster N.L., Benson D.F., Goldfarb L.G., Brown P. Familial Creutzfeldt–Jakob disease with a five-repeat octapeptide insert mutation. Neurology. 1996;47:727–733. doi: 10.1212/WNL.47.3.727. PubMed DOI

Capellari S., Vital C., Parchi P., Petersen R.B., Ferrer X., Jarnier D., Pegoraro E., Gambetti P., Julien J. Familial prion disease with a novel 144-bp insertion in the prion protein gene in a Basque family. Neurology. 1997;49:133–141. doi: 10.1212/WNL.49.1.133. PubMed DOI

Collinge J., Brown J., Hardy J., Mullan M., Rossor M.N., Baker H., Crow T.J., Lofthouse R., Poulter M., Ridley R., et al. Inherited prion disease with 144 base pair gene insertion. 2. Clinical and pathological features. Brain. 1992;115:687–710. doi: 10.1093/brain/115.3.687. PubMed DOI

Brown P., Goldfarb L.G., McCombie W.R., Nieto A., Squillacote D., Sheremata W., Little B.W., Godec M.S., Gibbs C.J., Gajdusek D.C. Atypical Creutzfeldt-Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene. Neurology. 1992;42:422. doi: 10.1212/WNL.42.2.422. PubMed DOI

Goldfarb L.G., Brown P., McCombie W.R., Goldgaber D., Swergold G.D., Wills P.R., Cervenakova L., Baron H., Gibbs C.J., Gajdusek D.C. Transmissible familial Creutzfeldt–Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc. Natl. Acad. Sci. USA. 1991;88:10926–10930. doi: 10.1073/pnas.88.23.10926. PubMed DOI PMC

Krasemann S., Zerr I., Weber T., Poser S., Kretzschmar H., Hunsmann G., Bodemer W. Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene. Brain Res. 1995;34:173–176. doi: 10.1016/0169-328X(95)00175-R. PubMed DOI

Vital C., Gray F., Vital A., Parchi P., Capellari S., Petersen R.B., Ferrer X., Jarnier D., Julien J., Gambetti P. Prion encephalopathy with insertion of octapeptide repeats: The number of repeats determines the type of cerebellar deposits. Neuropathol. Appl. Neurobiol. 1998;24:125–130. doi: 10.1046/j.1365-2990.1998.00098.x. PubMed DOI

Webb T.E.F., Poulter M., Beck J., Uphill J., Adamson G., Campbell T., Linehan J., Powell C., Brandner S., Pal S., et al. Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series. Brain. 2008;131:2632–2646. doi: 10.1093/brain/awn202. PubMed DOI PMC

Liberski P.P. Amyloid plaques in transmissible spongiform encephalopathies (prion diseases) Folia Neuropathol. 2004;42(Suppl. B):109–119. PubMed

Liberski P.P., Bratosiewicz J., Waliś A., Kordek R., Jeffrey M., Brown P. A special report I. Prion protein (PrP)--amyloid plaques in the transmissible spongiform encephalopathies, or prion diseases revisited. Folia Neuropathol. 2001;39:217–235. PubMed

Liberski P.P., Sikorska B., Lindenbaum S., Goldfarb L.G., McLean C., Hainfellner J.A., Brown P. Kuru: Genes, cannibals and neuropathology. J. Neuropathol. Exp. Neurol. 2012;71:92–103. doi: 10.1097/NEN.0b013e3182444efd. PubMed DOI PMC

Will R., Ironside J., Zeidler M., Estibeiro K., Cousens S., Smith P., Alperovitch A., Poser S., Pocchiari M., Hofman A. A new variant of Creutzfeldt–Jakob disease in the UK. Lancet. 1996;347:921–925. doi: 10.1016/S0140-6736(96)91412-9. PubMed DOI

Ironside J.W., E Bell J. Florid plaques and new variant Creutzfeldt–Jakob disease. Lancet. 1997;350:1475. doi: 10.1016/S0140-6736(05)64239-0. PubMed DOI

Ironside J.W., Head M.W., McCardle L., Knight R. Neuropathology of variant Creutzfeldt–Jakob disease. Acta Neurobiol. Exp. 2002;62:175–182. doi: 10.1016/S1631-0691(02)01381-1. PubMed DOI

World Federation of Scientists Visualization of a Battlefield: The Pathology of Human Transmissible Spongiform Encephalopathies by Budka H. [(accessed on 14 November 2020)]; Available online: http://www.federationofscientists.org/PMPanels/TSE/Visuals.php.

Ghetti B., Dlouhy S.R., Giaccone G., Bugiani O., Frangione B., Farlow M.R., Tagliavini F. Gerstmann–Sträussler–Scheinker disease and the Indiana kindred. Brain Pathol. 1995;5:61–75. doi: 10.1111/j.1750-3639.1995.tb00578.x. PubMed DOI

Ferrer I., Carmona M., Blanco R., Recio M., Segundo R. Gerstmann–Straüssler–Scheinker PRNP P102L-129V mutation. Transl. Neurosci. 2011;2:23–32. doi: 10.2478/s13380-011-0001-x. DOI

Thal D.R., Rüb 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

Alzheimer's Disease as a Membrane Dysfunction Tauopathy? New Insights into the Amyloid Cascade Hypothesis

Extracellular Prion Protein Aggregates in Nine Gerstmann-Sträussler-Scheinker Syndrome Subjects with Mutation P102L: A Micromorphological Study and Comparison with Literature Data

Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer's and Creutzfeldt-Jakob Disease: A Micromorphological Pilot Study on 20 Brains