P1-035: Exogenous induction of Abeta-amyloidosis: Peripheral and stainless-steel-wire inoculations

Abstract

Key pathologic characteristics of Alzheimer's disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillar aggregates of the amyloid-beta peptide (Aβ), and intracellular accumulation of abnormally phosphorylated tau protein associated with widespread neurodegeneration. The misfolding and aggregation of these proteins in the pathogenesis of AD is well-established, but little is known about how protein aggregation is initiated in vivo. We have recently shown that intracerebral injection of dilute extracts from the brains of humans with AD or from aged amyloid precursor protein (APP) transgenic (tg) mice induces cerebral β-amyloidosis and associated pathology in young APP tg mice in a time- and concentration-dependent manner (Meyer-Luehmann et al., Science 313: 1781, 2006). As these observations are reminiscent of prion diseases, we investigated whether β-amyloidosis can be induced via peripheral inoculation routes. Since prion diseases can also be transmitted intracerebrally via contaminated steel material such as surgical instruments, we additionally studied this potential route of Aβ-seeding. APP23 tg mice (4–5 mo of age) were used as a model system to assess induction of Aβ-amyloidosis. The following routes of peripheral inoculation were investigated: oral, intraperitoneal, intravenous, intraocular and intranasal. Additionally, stainless-steel wires, previously coated with Aβ-rich brain extract, were implanted intracerebrally. Mice were analyzed 4–8 months later. None of the peripheral application routes yielded detectable induction of cerebral β-amyloidosis. In contrast, intracerebral implantation of Aβ-extract-coated wires was sufficient to induce β-amyloidosis in the vicinity of the steel wire, whereas wires coated with brain extract from a wildtype mouse did not induce Aβ deposition in the host. No evidence was found that Aβ-amyloidosis can be induced by the peripheral administration of Aβ-rich extracts. However, amyloid-induction via intracerebrally implanted stainless-steel wires coated with Aβ-rich brain extracts raises the possibility that contaminated surgical instruments are a potential source of Aβ seeds and induction of cerebral β-amyloidosis. A study investigating the effects of standard disinfection methods for surgical instruments on preventing the Aβ-seeding potential is currently ongoing.