Formaldehyde-fixed brain tissue from spontaneously ill α-synuclein transgenic mice induces fatal α-synucleinopathy in transgenic hosts.

Abstract

attributes of prions, namely the resistance to inactivation by formaldehyde. The histopathological hallmarks of α-synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are intracellular Lewy bodies and Lewy neurites, comprised primarily of hyperphosphorylated α-synuclein [3]. In PD brain, α-synuclein lesions progress in a stereotypic manner [1]. The underlying mechanism is hypothesized to be cell-to-cell transmission of aggregated α-synuclein that initiates a cascade of progressive α-synuclein misfolding and aggregation reminiscent of prion disorders [4, 5]. Experimentally similar to Aβ inoculations, α-synuclein lesions can be induced in susceptible hosts by intracerebral inoculation of extracts from human brains affected by α-synucleinopathies or brains from spontaneously ill α-synuclein tg mice containing aggregated α-synuclein [6, 7]. Given the astonishing findings of formaldehyde-resistant Aβ seeds [2], we asked whether this is also true for α-synuclein seeds. Compelling evidence suggests that in a variety of neurodegenerative diseases the induction and spreading of proteinaceous lesions involve a prion-like seeding mechanism [5]. Experimentally and for Alzheimer’s disease (AD), it has been shown that cerebral β-amyloidosis can be instigated in susceptible hosts [i.e., young amyloid precursor protein (APP) transgenic (tg) mice] by the intracerebral injections of diluted extracts from β-amyloid-laden brains of aged APP tg mice or AD patients. The β-amyloid-inducing agent in the inoculate is an aggregated form of the amyloid-β peptide (Aβ) [8]. Remarkably, we recently reported that extracts of formaldehyde-fixed brains of aged APP tg mice or AD patients also induces cerebral β-amyloidosis [2]. Thus, Aβ seeds share one of the most remarkable