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Cited by 82Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Deposition of Hyperphosphorylated Tau in Cerebellum of PS1 E280A Alzheimer's Disease

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Sepulveda‐Falla, Diego, Matschke, Jakob, Bernreuther, Christian, Hagel, Christian, Puig, Berta, Villegas, Andres, Garcia, Gloria, Zea, Julian +4 more·2011·Brain Pathology
DOI 10.1111/j.1750-3639.2010.00469.xPMC PMC8094246
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Abstract

Early‐onset familial Alzheimer's disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimer's disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.

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  1. [1]1. Anheim M, Hannequin D, Boulay C, Martin C, Campion D, Tranchant C (2007) Ataxic variant of Alzheimer's disease caused by Pro117Ala PSEN1 mutation. J Neurol Neurosurg Psychiatry 78:1414–1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. [2]2. Ardila A, Lopera F, Rosselli M, Moreno S, Madrigal L, Arango‐Lasprilla JC et al (2000) Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin‐1 mutation. Arch Clin Neuropsychol 15:515–528. [PubMed] [Google Scholar]
  3. [3]3. Baki L, Neve RL, Shao Z, Shioi J, Georgakopoulos A, Robakis NK (2008) Wild‐type but not FAD mutant presenilin‐1 prevents neuronal degeneration by promoting phosphatidylinositol 3‐kinase neuroprotective signaling. J Neurosci 28:483–490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. [4]4. Bird TD (2008) Genetic aspects of Alzheimer's disease. Genet Med 10:231–239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. [7]7. Burns A, Iliffe S (2009) Alzheimer's disease. BMJ 338:b158. [DOI] [PubMed] [Google Scholar]
  6. [8]8. Cras P, Smith MA, Richey PL, Siedlak SL, Mulvihill P, Perry G (1995) Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross‐linking in Alzheimer's disease. Acta Neuropathol 89:291–295. [DOI] [PubMed] [Google Scholar]
  7. [9]9. De Strooper B (2007) Loss‐of‐function presenilin mutations in Alzheimer's disease. Talking point on the role of presenilin mutations in Alzheimer's disease. EMBO Rep 8:141–146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [10]10. Debatin L, Streffer J, Geissen M, Matschke J, Aguzzi A, Glatzel M (2008) Association between deposition of beta‐amyloid and pathological prion protein in sporadic Creutzfeldt‐Jakob disease. Neurodegener Dis 5:347–354. [DOI] [PubMed] [Google Scholar]
  9. [12]12. Dermaut B, Kumar‐Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J et al (2004) A novel presenilin‐1 mutation associated with Pick's disease but not beta‐amyloid plaques. Ann Neurol 55:617–626. [DOI] [PubMed] [Google Scholar]
  10. [13]13. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer's disease. Acta Neuropathol 118:5–36. [DOI] [PubMed] [Google Scholar]
  11. [14]14. Ferrer I, Gomez‐Isla T, Puig B, Freixes M, Ribe E, Dalfo E, Avila J (2005) Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. Curr Alzheimer Res 2:3–18. [DOI] [PubMed] [Google Scholar]
  12. [15]15. Finckh U, Muller‐Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W et al (2000) High prevalence of pathogenic mutations in patients with early‐onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66:110–117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [16]16. Fukutani Y, Sasaki K, Mukai M, Matsubara R, Isaki K, Cairns NJ (1997) Neurons and extracellular neurofibrillary tangles in the hippocampal subdivisions in early‐onset familial Alzheimer's disease: a case study. Psychiatry Clin Neurosci 51:227–231. [DOI] [PubMed] [Google Scholar]
  14. [17]17. Gallyas F (1971) Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung 19:1–8. [PubMed] [Google Scholar]
  15. [18]18. Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A (1995) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease. Neurology 45(3 Pt 1):461–466. [DOI] [PubMed] [Google Scholar]
  16. [19]19. Glatzel M, Pekarik V, Luhrs T, Dittami J, Aguzzi A (2002) Analysis of the prion protein in primates reveals a new polymorphism in codon 226 (Y226F). Biol Chem 383:1021–1025. [DOI] [PubMed] [Google Scholar]
  17. [20]20. Gomez‐Isla T, Growdon WB, McNamara MJ, Nochlin D, Bird TD, Arango JC et al (1999) The impact of different presenilin‐1 and presenilin‐2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype‐modifying factors. Brain 122(Pt 9):1709–1719. [DOI] [PubMed] [Google Scholar]
  18. [21]21. Herrmann M, Golombowski S, Krauchi K, Frey P, Mourton‐Gilles C, Hulette C et al (1999) ELISA quantitation of phosphorylated tau protein in the Alzheimer's disease brain. Eur Neurol 42:205–210. [DOI] [PubMed] [Google Scholar]
  19. [22]22. Iqbal K, Grundke‐Iqbal I (2008) Alzheimer's neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J Cell Mol Med 12:38–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [23]23. Jalbert JJ, Daiello LA, Lapane KL (2008) Dementia of the Alzheimer's type. Epidemiol Rev 30:15–34. [DOI] [PubMed] [Google Scholar]
  21. [24]24. Jellinger KA, Bancher C (1998) Neuropathology of Alzheimer's disease: a critical update. J Neural Transm Suppl 54:77–95. [DOI] [PubMed] [Google Scholar]
  22. [25]25. Johnson‐Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R et al (1997) Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 94:1550–1555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [26]26. Karlstrom H, Brooks WS, Kwok JB, Broe GA, Kril JJ, McCann H et al (2008) Variable phenotype of Alzheimer's disease with spastic paraparesis. J Neurochem 104:573–583. [DOI] [PubMed] [Google Scholar]
  24. [27]27. Koffie RM, Meyer‐Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia‐Alloza M et al (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106:4012–4017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [28]28. Larner AJ (1997) The cerebellum in Alzheimer's disease. Dement Geriatr Cogn Disord 8:203–209. [DOI] [PubMed] [Google Scholar]
  26. [29]29. Larner AJ, Doran M (2006) Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin‐1 gene. J Neurol 253:139–158. [DOI] [PubMed] [Google Scholar]
  27. [30]30. Larner AJ, Doran M (2009) Genotype‐phenotype relationships of presenilin‐1 mutations in Alzheimer's disease: an update. J Alzheimers Dis 17:259–265. [DOI] [PubMed] [Google Scholar]
  28. [31]31. Larner AJ, Ray PS, Doran M (2007) The R269H mutation in presenilin‐1 presenting as late‐onset autosomal dominant Alzheimer's disease. J Neurol Sci 252:173–176. [DOI] [PubMed] [Google Scholar]
  29. [32]32. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC et al (1996) The E280A presenilin‐1 Alzheimer's mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 2:1146–1150. [DOI] [PubMed] [Google Scholar]
  30. [33]33. Li YT, Woodruff‐Pak DS, Trojanowski JQ (1994) Amyloid plaques in cerebellar cortex and the integrity of Purkinje cell dendrites. Neurobiol Aging 15:1–9. [DOI] [PubMed] [Google Scholar]
  31. [36]36. Rollenhagen A, Lubke JH (2006) The morphology of excitatory central synapses: from structure to function. Cell Tissue Res 326:221–237. [DOI] [PubMed] [Google Scholar]
  32. [37]37. Schwab C, Akiyama H, McGeer EG, McGeer PL (1998) Extracellular neurofibrillary tangles are immunopositive for the 40 carboxy‐terminal sequence of beta‐amyloid protein. J Neuropathol Exp Neurol 57:1131–1137. [DOI] [PubMed] [Google Scholar]
  33. [38]38. Shepherd C, McCann H, Halliday GM (2009) Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol 118:37–52. [DOI] [PubMed] [Google Scholar]
  34. [39]39. Steiner H, Fluhrer R, Haass C (2008) Intramembrane proteolysis by gamma‐secretase. J Biol Chem 283:29627–29631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. [40]40. Tabaton M, Cammarata S, Manetto V, Perry G, Mancardi G (1989) Tau‐reactive neurofibrillary tangles in cerebellar cortex from patients with Alzheimer's disease. Neurosci Lett 103:259–262. [DOI] [PubMed] [Google Scholar]
  36. [41]41. Tang‐Wai DF, Graff‐Radford NR, Boeve BF, Dickson DW, Parisi JE, Crook R et al (2004) Clinical, genetic and neuropathologic characteristics of posterior cortical atrophy. Neurology 63:1168–1174. [DOI] [PubMed] [Google Scholar]
  37. [42]42. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta‐deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800. [DOI] [PubMed] [Google Scholar]
  38. [43]43. Van Vickle GD, Esh CL, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC et al (2008) Presenilin‐1 280Glu ‐ >Ala mutation alters C‐terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease. Mol Med 14:184–194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. [44]44. Verbeek MM, Ruiter DJ, de Waal RM (1997) The role of amyloid in the pathogenesis of Alzheimer's disease. Biol Chem 378:937–950. [DOI] [PubMed] [Google Scholar]
  40. [45]45. Verdile G, Gnjec A, Miklossy J, Fonte J, Veurink G, Bates K et al (2004) Protein markers for Alzheimer's disease in the frontal cortex and cerebellum. Neurology 63:1385–1392. [DOI] [PubMed] [Google Scholar]
  41. [47]47. Wang HY, D'Andrea MR, Nagele RG (2002) Cerebellar diffuse amyloid plaques are derived from dendritic Abeta42 accumulations in Purkinje cells. Neurobiol Aging 23:213–223. [DOI] [PubMed] [Google Scholar]
  42. [48]48. Woodhouse A, Shepherd CE, Sokolova A, Carroll VL, King AE, Halliday GM et al (2009) Cytoskeletal alterations differentiate presenilin‐1 and sporadic Alzheimer's disease. Acta Neuropathol 117:19–29. [DOI] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article.

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Authors
Sepulveda‐Falla, D., Matschke, J., Bernreuther, C., Hagel, C., Puig, B., Villegas, A., Garcia, G., Zea, J., Gomez‐Mancilla, B., Ferrer, I., Lopera, F., & Glatzel, M.
Affiliations
  • University Medical Center Hamburg-Eppendorf (DE)
  • Novartis (Switzerland) (CH)
  • Universidad de Antioquia (CO)
ORCID
Venue
Brain Pathology
Publisher
Wiley
Published
2011-01-27
Volume
21
Issue
4
Pages
452-463
ISSN
  • 1015-6305 (ISSN-L)
  • 1750-3639
DOI
10.1111/j.1750-3639.2010.00469.x
PMC
PMC8094246
OpenAlex
W1596552964
Cited by
82
References
6
Citations by year
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FWCI
4.12
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Brain Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repository University of Antioquia (University of Antioquia) (publishedVersion, cc-by)
  • Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
presenilin-1 E280A mutation, early-onset familial Alzheimer's disease, cerebellar involvement, hyperphosphorylated tau, amyloid-beta deposition, amyloid-beta 42, cerebellar ataxia, Purkinje cells, stress kinases, clinical phenotype
MeSH terms
Aged, Alzheimer Disease, Cerebellum, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Humans, Male, Middle Aged, Mutation, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Age of Onset, Microscopy, Electron, Transmission, Presenilin-1, Plaque, Amyloid

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