Aβ seeds resist inactivation by formaldehyde

Abstract

Cerebral β-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated β-amyloid (Aβ) into young, pre-depositing Aβ precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated Aβ itself. Here we report that the β-amyloid-inducing activity of Alzheimer’s disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated Aβ are maintained in fixed tissues. The resistance of Aβ seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of Aβ aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.

Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein

“…Thus, both PrP Sc and assembled Ab bound tightly to stainless-steel wires, and after their brain implantation, replication occurred, and prion-specific pathological changes ensued (41,42). Assembled Ab and a-synuclein were also resistant to inactivation by formaldehyde (43,44).…”

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

“…Boiling of brain homogenates harboring Aβ seeds reduces the seeding activity, but does not abolish it [87]. Likewise, formaldehyde treatment of brain tissue harboring Aβ aggregates reduces, but does not abolish, seeding activity [39]. It was found that insoluble Aβ seeds are relatively proteinase K (PK) resistant with 80 % of insoluble Aβ in brain homogenates remaining detectable and retaining seeding activity after 30 min of PK treatment.…”

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

“…The fixed brain samples retained their seeding potential, even after as long as 2 yr in formaldehyde (Fritschi et al 2014a). Additionally, the spectral patterns of luminescent conjugated oligothiophenes bound to Ab indicated that the molecular architecture of the Ab seeds was maintained in fixed tissue and could be faithfully transmitted to the host mice (Fritschi et al 2014a). …”