title: The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ.
abstract: BACKGROUND
  The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.
  
  
  RESULTS
  Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.
  
  
  CONCLUSIONS
  In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
authors.affiliation: Department of Public Health/Geriatrics, Uppsala University Hospital, Uppsala University, Box 609, SE-751 25, Uppsala, Sweden. Martin.Ingelsson@pubcare.uu.se.
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Maciej
authors.initials: M
authors.lastname: Lalowski
authors.forename: Nenad
authors.initials: N
authors.lastname: Bogdanovic
authors.forename: Ola
authors.initials: O
authors.lastname: Philipson
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: David
authors.initials: D
authors.lastname: Nochlin
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Brundin
authors.forename: Tommie
authors.initials: T
authors.lastname: Olofsson
authors.forename: Rabah
authors.initials: R
authors.lastname: Soliymani
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Lars N G
authors.initials: LN
authors.lastname: Nilsson
authors.forename: Hans
authors.initials: H
authors.lastname: Basun
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005190:Family; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013548:Sweden; D044465:White People / Q000235:genetics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor