The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation

Abstract

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

“…The turn structure formation in the Ala21-Ala30 region of the wild-type Aβ peptide, which is linked to the aggregation process, is less abundant in the structures of the E22Δ mutant-type Aβ40 and Aβ42 peptides in an aqueous solution environment. On the other hand, α-helix and 3 10 -helix abundances are larger in the C-terminal regions of the E22Δ mutant-type Aβ40 and Aβ42 peptides rather than the wild-type peptides. No stark differences are detected for the adopted β-sheet abundances in the C-terminal regions upon E22Δ mutation of Aβ42.…”

“…Furthermore, 3 10 -helix formation increases sharply for Ile31-Leu34 in the structures of the E22Δ mutant-type Aβ40 peptide in comparison to its wild-type form ( Figure 1A). On the other hand, 3 10 -helix formation is decreased by 11−14% at Ile31-Gly33 in Aβ42 upon E22Δ mutation ( Figure 1B). The β-sheet formation in the C-terminal region of the E22Δ mutant-type Aβ42 does not differ significantly from that of the wild-type Aβ42 that we reported most recently.…”

“…Structures with representative tertiary and secondary structure characteristics of the most favorable PMF basins (basin IA and IB) for each of the wild-and E22Δ mutant-type Aβ peptides are displayed next to the PMF surface. The secondary structure components of each peptide structure are displayed by the color of the peptide backbone: α-helix (blue), 3 10 -helix (gray), π-helix (purple), β-sheet (red), β-bridge (black), turn (yellow), and coil (white). …”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…The similar heights of the spheres, chain-like and annular protofibrils suggests that the spheres are the precursors of the others . Formation of annular protofibrils is promoted by a pathogenic mutation [APP (E693G)=Ab(E22G)] that is linked to familial AD and accelerates the oligomerization of Ab in vitro (Nilsberth et al 2001 ;Lashuel et al 2002a, b). Annular protofibrils represent only a small fraction of the total population of Ab protofibrils at any given time, which explains why these structures were missed or ignored in previous studies.…”

Proteostasis in cardiac health and disease

“…Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 .…”