Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

Abstract

The polymorphic b-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral b-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop b-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Ab40/Ab42 peptide ratio. To determine the nature of such b-amyloid morphotypes, b-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced b-amyloid deposition with the morphological, conformational, and Ab40/Ab42 ratio characteristics of b-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of b-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced b-amyloid deposits, although less prominent, and the induced deposits were similar to the b-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Ab in APP transgenic mice can be maintained by seeded conversion.

Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping

“…3A). Similar strain plasticity has been observed in other neurodegenerative diseases (1,27,28,(33)(34)(35)(36). Considering the quite different and more malleable appearance of the hSOD1 fibrils in vitro (Fig.…”

“…4 A and B). This coexistence distinguishes the hSOD1 D90A mice from previous disease models where the variation of strains is typically observed between individuals (1,34,35,41). Even so, the hSOD1 D90A mice highlight the notion that strain variation influences pathology, as previously observed for prions (27,28), and in patients and models for synucleopathies (33), Alzheimer's disease (1,35,36), and tauopathies (34).…”

Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients

“…2C). Different Aβ peptide ratios were also observed after inoculation of Tg(APP23) mice with brain extracts from two different Tg mouse models of AD (38).…”

“…Each of these peptides is likely to possess a different thermodynamic landscape with respect to conversion into a prion. The difficulties surrounding studies of Aβ prion strains are highlighted by a study using Tg(APP23) and Tg(APPPS1) mice; the former produces much more Aβ40 than Aβ42, whereas the latter produces the opposite (38). In our AD-inoculated mice, the most prominent strain-specific differences, including the relative amount of Aβ38 deposition, were observed in cerebral blood vessels but not parenchymal amyloid plaques.…”

Transmission des lésions amyloïdes de la maladie d’Alzheimer : apports des modèles animaux

“…Différentes morphologies de fibrilles Ab caractérisées par différentes structures moléculaires peuvent être obtenues in vitro et exercent des toxicités différentes dans des cultures cellulaires neuronales (Petkova et al 2005;Spirig et al 2014) y compris après plusieurs passages . In vivo, la morphologie et le motif des dépôts d'Ab (Kane et al 2000;Meyer-Luehmann et al 2006) ainsi que d'autres caractéristiques telles que la liaison des colorants sensibles à la conformation amyloïde (rouge Congo, thioflavine) ou le rapport Ab 40 /Ab 42 peuvent être transmis d'une lignée de souris transgéniques à l'autre suggérant un effet de souche (Heilbronner et al 2013). Finalement, des agrégats d'Ab provenant de patients avec des mutations génétiques différentes sur Ab ou sans mutation présentent une résistance distincte à la dénaturation (protéinase-K, chlorhydrate de guanidine, acide formique), un phénotype histologique et des rapports Ab 40 /Ab 42 différents suggérant des conformations Ab distinctes .…”