Exogenous seeding of cerebral β‐amyloid deposition in βAPP‐transgenic rats

Abstract

Deposition of the Aβ peptide in senile plaques and cerebral Aβ angiopathy can be stimulated in Aβ-precursor protein-transgenic mice by the intracerebral injection of dilute brain extracts containing aggregated Aβ seeds. Growing evidence implicates a prion-like mechanism of corruptive protein templating in this phenomenon, in which aggregated Aβ itself is the seed. Unlike prion disease, which can be induced de novo in animals that are unlikely to spontaneously develop the disease, previous experiments with Aβ seeding have employed animal models that, as they age, eventually will generate Aβ lesions in the absence of seeding. In the present study, we first established that a transgenic rat model expressing human Aβ-precursor protein (APP21 line) does not manifest endogenous deposits of Aβ within the course of its median lifespan (30 months). Next, we injected 3-month-old APP21 rats intrahippocampally with dilute Alzheimer brain extracts containing aggregated Aβ. After a 9-month incubation period, these rats had developed senile plaques and cerebral Aβ angiopathy in the injected hippocampus, whereas control rats remained free of such lesions. These findings underscore the co-dependence of agent and host in governing seeded protein aggregation, and show that cerebral Aβ-amyloidosis can be induced even in animals that are relatively refractory to the spontaneous origination of parenchymal and vascular deposits of Aβ.

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…Aβ injection was previously reported to trigger intracellular Aβ aggregation in transgenic animals, and nonhuman primates, both of which express human sequence Aβ [33,34]. Mice and rats have a different sequence of Aβ that does not precipitate, even in the presence of zinc [35].…”

The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

“…To induce Ab deposition in the in vivo seeding model, it is necessary for the host animal to express seeding-capable Ab (Kane et al 2000;Meyer-Luehmann et al 2006;Morales et al 2012;Rosen et al 2012). In earlier studies, transgenic mouse models that eventually develop endogenous Ab lesions as they age were used.…”

The aggregation of mutant p53 produces prion-like properties in cancer

“…The intracerebral injection of brain homogenates derived from AD patients induces disease in transgenic mice and rats expressing the amyloid protein (Aβ precursor). 37,38 Mutant forms of SOD1 and TDP-43 are also able to seed misfolding of the wild-type protein both in vitro and in cell cultures. 4,39 Self-propagation and template misfolding are basic characteristics of a prion; however, the ability to replicate in a new host is another defining characteristic of the prion.…”