C. Nilsberth et al., The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation, NAT NEUROSC, 4(9), 2001, pp. 887-893
Several pathogenic Alzheimer's disease (AD) mutations have been described,
all of which cause increased amyloid beta -protein (A beta) levels. Here we
present studies of a pathogenic amyloid precursor protein (APP) mutation,
located within the A beta sequence at codon 693 (E693G), that causes AD in
a Swedish family. Carriers of this 'Arctic' mutation showed decreased A bet
a 42 and A beta 40 levels in plasma. Additionally, low levels of A beta 42
were detected in conditioned media from cells transfected with APP(E693G).
Fibrillization studies demonstrated no difference in fibrillization rate, b
ut A beta with the Arctic mutation formed protofibrils at a much higher rat
e and in larger quantities than wild-type (wt) A beta. The finding of incre
ased protofibril formation and decreased A beta plasma levels in the Arctic
AD may reflect an alternative pathogenic mechanism for AD involving rapid
A beta protofibril formation leading to accelerated buildup of insoluble A
beta intra- and/or extracellularly.