Aβ oligomers trigger and accelerate Aβ seeding

Abstract

Aggregation of amyloid‐β (Aβ) that leads to the formation of plaques in Alzheimer's disease (AD) occurs through the stepwise formation of oligomers and fibrils. An earlier onset of aggregation is obtained upon intracerebral injection of Aβ‐containing brain homogenate into human APP transgenic mice that follows a prion‐like seeding mechanism. Immunoprecipitation of these brain extracts with anti‐Aβ oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aβ deposition was still evident. Here, we establish that, together with Aβ monomers, Aβ oligomers trigger the initial phase of Aβ seeding and that the depletion of oligomeric Aβ delays the aggregation process, leading to a transient reduction of seed‐induced Aβ deposits. This work extends the current knowledge about the role of Aβ oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aβ aggregation in vivo. We conclude that Aβ oligomers are important for the early initiation phase of the seeding process.

Aβ Seeding as a Tool to Study Cerebral Amyloidosis and Associated Pathology

“…Interestingly, sonication and thus fragmentation of the insoluble fraction into smaller and more soluble Aβ seeds, enhanced the seeding activity of the inoculum, consistent with results from fragmentation studies (Jarrett and Lansbury, 1993; Falsig et al, 2008; Knowles et al, 2009; Xue et al, 2009). In line with the previous mentioned studies, Aβ oligomers seem to be important for the initiation of Aβ aggregation especially for the early phase of the seeding process (Katzmarski et al, 2019). According to another study, the Aβ seeding potency of the brain extracts is highest at the very early stage of cerebral amyloidosis (Ye et al, 2017).…”

Mechanism of Cellular Production and in Vivo Seeding Effects of Hexameric β-Amyloid Assemblies

“…An earlier onset of Aβ aggregation in this model was previously reported upon single intracerebral injection of brain homogenates containing oligomeric Aβ, following a prion-like seeding mechanism [71]. Aβ oligomers have been further suggested as early initiating actors of the seeding process, as their depletion by passive immunization delays Aβ aggregation and leads to a transient reduction of seed-induced Aβ deposition [72]. Here, our study has the advantage of focusing on a speci c cell-derived Aβ aggregate, that not only is an oligomeric entity of its own but also suspected, based on in vitro studies, to be heavily involved in the processes of nucleation and seeding [15,29].…”

Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

“…An earlier onset of A aggregation in this model was previously reported upon single intracerebral injection of brain homogenates containing oligomeric A, following a prion-like seeding mechanism [71]. A oligomers have been further suggested as early initiating actors of the seeding process, as their depletion by passive immunization delays A aggregation and lead to a transient reduction of seed-induced A deposition [72]. Here, our study has the advantage of focusing on a specific cell-derived A aggregate, that not only is an oligomeric entity of its own but also suspected, based on in vitro studies, to be heavily involved in the processes of nucleation and seeding [15,29].…”