title: Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease.
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.
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Diego
authors.initials: D
authors.lastname: Sepulveda-Falla
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.forename: Christian
authors.initials: C
authors.lastname: Bernreuther
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Berta
authors.initials: B
authors.lastname: Puig
authors.forename: Andres
authors.initials: A
authors.lastname: Villegas
authors.forename: Gloria
authors.initials: G
authors.lastname: Garcia
authors.forename: Julian
authors.initials: J
authors.lastname: Zea
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism* / Q000648:ultrastructure*
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins