title: Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aβ and mutated human Alzheimer's precursor protein (APP).
abstract: OBJECTIVE
  Alzheimer's disease and the transmissible spongiform encephalopathies or prion diseases accumulate misfolded and aggregated forms of neuronal cell membrane proteins. Distinctive membrane lesions caused by the accumulation of disease-associated prion protein (PrP(d)) are found in prion disease but morphological changes of membranes are not associated with Aβ in Alzheimer's disease. Membrane changes occur in all prion diseases where PrP(d) is attached to cell membranes by a glycosyl-phosphoinositol (GPI) anchor but are absent from transgenic mice expressing anchorless PrP(d). Here we investigate whether GPI membrane attached Aβ may also cause prion-like membrane lesions.
  
  
  METHODS
  We used immunogold electron microscopy to determine the localization and pathology of Aβ accumulation in groups of transgenic mice expressing anchored or unanchored forms of Aβ or mutated human Alzheimer's precursor protein.
  
  
  RESULTS
  GPI attached Aβ did not replicate the membrane lesions of PrP(d). However, as with PrP(d) in prion disease, Aβ peptides derived from each transgenic mouse line initially accumulated on morphologically normal neurite membranes, elicited rapid glial recognition and neurite Aβ was transferred to attenuated microglial and astrocytic processes.
  
  
  CONCLUSIONS
  GPI attachment of misfolded membrane proteins is insufficient to cause prion-like membrane lesions. Prion disease and murine Aβ amyloidosis both accumulate misfolded monomeric or oligomeric membrane proteins that are recognized by glial processes and acquire such misfolded proteins prior to their accumulation in the extracellular space. In contrast to prion disease where glial cells efficiently endocytose PrP(d) to endolysosomes, activated microglial cells in murine Aβ amyloidosis are not as efficient phagocytes.
authors.affiliation: Animal Health and Veterinary Laboratories Agency, Lasswade Laboratory, Penicuik, Midlothian, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Jeffrey
authors.affiliation: Animal Health and Veterinary Laboratories Agency, Lasswade Laboratory, Penicuik, Midlothian, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: McGovern
authors.affiliation: Neurobiology Division, Roslin Institute & R(D)SVS, University of Edinburgh, Roslin, Midlothian, UK.
authors.forename: Rona
authors.initials: R
authors.lastname: Barron
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Baumann
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure*; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000648:ultrastructure*; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Aβ; glycosyl-phosphoinositol; microglia; mutant Alzheimer's precursor protein; prion disease; protein misfolding