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

Abstract

Correspondence: m.b.koopman@uu.nl and s.g.d.rudiger@uu.nl Alzheimer's 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 Alzheimer's Disease show very specific derailment of the protein quality control network. We performed a metaanalysis on the Alzheimer's 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 cochaperones -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 Alzheimer's 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.

Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk

“…Thus, mechanisms inducing chromatin modification, transcription and splicing were highly reduced in them. Amongst the heat shock proteins, we found Hspa4 to be upregulated which ensured that it maintained the disaggregating property of any misfolded proteins, thereby, preventing further damage and inducing tissue integrity 89 . Additionally, it also helped in sulfatase gene (Sumf2) maintenance which is associated with modulation of tissue homeostasis 90 .…”

Molecular mechanisms of amyloid formation in living systems

“…142 In brain tissue of Alzheimer's patients, most chaperones also remain unchanged, but Hsp90 paralogs are selectively downregulated. 162 For specic client proteins, such disturbances may be sufficient to exceed their solubility limits. Computational predictions have revealed that many disease-associated proteins are expressed at levels close to their solubility, 163 meaning that subtle perturbations may be sufficient to cross this threshold.…”

Secreted Chaperones in Neurodegeneration

“…This chaperone colocalizes with extracellular amyloid deposits found in CAA, a common comorbid condition in AD ( Wilhelmus et al, 2009 ). A recent meta-analysis of protein quality control pathways in the AD brain clearly shows upregulation of sHSPs ( Koopman and Rüdiger, 2020 ). Multiple immunohistochemical studies have shown that sHsps are present within extracellular amyloid plaques ( Wilhelmus et al, 2006 ; Ojha et al, 2011 ; see Reddy et al, 2018 for review).…”