1. Amyloid β aggregation is coupled to cellular metabolism and intramitochondrial proteostasis
- Author
-
Wagner Valladolid, Sara
- Subjects
- Alzheimer's disease ; Ageing ; Amyloid ß ; Mitochondria
- Abstract
As human lifespans grow longer due to advances in modern medicine, age-associated disorders characterised by peptide aggregation, such as Alzheimer's disease (AD), become more prevalent. Research efforts have aimed to unveil the underlying mechanism of disease pathogenesis in order to develop potential therapies. In particular, reports have focused on studying the nature and kinetics of peptide aggregation and finding ways to inhibit this process. However, little is known about the dynamics of protein self-assembly, and effective inhibitors have not yet been identified. This lack of success can be associated with limitations affecting the standard techniques employed to study peptide self-assembly. Drawbacks include the inability to bridge in vitro, cellular and in vivo studies, lack of reproducibility, false read-outs caused by artefacts, and high cost. Here, we circumvent issues associated with conventional methods by using a cutting-edge platform that quantifies fluorescence lifetime decay of fluorophores conjugated to aggregating proteins in living systems. Taking advantage of this sensor, we demonstrate that two novel aggregation-prone proteins, Ras-like GTP-binding protein rhoA and Casein kinase I isoform alpha, form amyloid structures in a Caenorhabditis elegans model, with ageing. Using this system, we monitor the aggregation of the Amyloid β (1-42) (Aβ42) protein involved in AD, and we show that a new anti-aggregation compound, MJ040X, can suppress Aβ42 self-assembly in cellular and whole organism disease models. Besides, we demonstrate that mitochondrial function declines and metabolism shifts towards glycolysis in a cellular model of AD that overexpresses Aβ42 with the E22G mutation. Moreover, we successfully deliver exogenous healthy mitochondria into these cells, which results in a reduction in Aβ42 aggregation. We also investigate the direct effort of intramitochondrial proteostasis on Aβ42 aggregation by performing a range of pharmacological assays. Overall, this work demonstrates a two-way association between Aβ42 self-assembly and mitochondrial function and proposes mitochondrial transplantation as a novel method to combat Alzheimer's disease.
- Published
- 2021