Alzheimer cells on their way to derailment show selective changes in protein quality control network

• Published in: bioRxiv
• Main Authors: Koopman, Margreet B, Rüdiger, Stefan Gd
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.05.2020
• Subjects: Alzheimer's disease; Autophagy; Brain; Cell death; Chaperones; Heat shock proteins; Hsp70 protein; Hsp90 protein; Neurodegenerative diseases; Neurofibrillary tangles; Phagocytosis; Proteasomes; Protein folding; Protein interaction; Proteomes; Quality control; Small heat shock proteins; Tau protein
• DOI: 10.1101/2020.05.17.099465

Alzheimers Disease is driven by protein aggregation and is characterised by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here we describe that brain cells in Alzheimers Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimers Disease Proteasome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison with age-matched controls. We noted that levels of all paralogues of the conserved Hsp90 chaperone family are reduced, while most other chaperones, or their regulatory co-chaperones, do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3, which links the Hsp70 system to autophagy - and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channelling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimes brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analysed, may represent a last, unsuccessful attempt to advert neuronal cell death. Competing Interest Statement The authors have declared no competing interest.