The Arctic A beta PP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated A beta

Background: The Arctic mutation (p.E693G/p.E22G) fs within the beta-amyloid (A beta) region of the beta-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: A beta deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative A beta aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that A beta deposits contained variably truncated and modified wild type and mutated A beta 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 A beta surrounded by coronas immunopositive for A beta(x-42). In the fourth patient plaque centres contained almost no A beta 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 A beta plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the A beta plaques appeared relatively intact. Conclusions: In Arctic AD brain differentially truncated abundant A beta 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 A beta does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular A beta oligomers are more neurotoxic than extracellular A beta 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.