Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease

Brain Pathol. 2011 Jul;21(4):452-63. doi: 10.1111/j.1750-3639.2010.00469.x. Epub 2011 Jan 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / ultrastructure
  • Cerebellum / metabolism*
  • Cerebellum / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Male
  • Microscopy, Electron, Transmission
  • Middle Aged
  • Mutation
  • Phosphorylation
  • Plaque, Amyloid / ultrastructure
  • Presenilin-1 / genetics
  • tau Proteins / metabolism*
  • tau Proteins / ultrastructure*

Substances

  • Amyloid beta-Peptides
  • PSEN1 protein, human
  • Presenilin-1
  • tau Proteins