Chaperone signalling complexes in Alzheimer's disease

Abstract

Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid-β accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

Factor V Activator from Daboia russelli russelli Venom Destabilizes β-Amyloid Aggregate, the Hallmark of Alzheimer Disease

“…Recent reports showed that low molecular weight drugs including small organic molecules, peptides, small molecular chaperones, enzymes, and antibodies are gaining attention for the treatment of AD (11)(12)(13). The concept of using proteases and peptides as therapeutic agents is common.…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…Whereby, molecular chaperones make sure that other proteins arrive safely and are functional at their destination within the cell. They also ensure that proteins deemed to be 'ill-behaved' or abnormal are destroyed [249][250][251].…”

“…Hsps with a molecular weight of 60 kDa or more possess an ATPbinding site and are actively involved in the process of refolding misfolded proteins. Small Hsps, with a molecular weight of 40 kDa or less, lack this ATP-binding site and assist the classic Hsps in their refolding function [249][250][251]. Several heat shock proteins can be found in mitochondria, namely the classic Hsps Hsp60, mtHsp70 (mortallin), mtHsp90 (TRAP-1) and Hsp78 and small Hsps Hsp10, Hsp27, αB-crystallin, Hsp22, mtHsp40 [251][252][253][254][255].…”

“…Moreover, a similar mechanism of action could occur in the processing of other pathological proteins involved in AD development, e.g. tau-protein and APP [250,259,260]. However, it remains to be elucidated, whether these interactions take place inside the mitochondria and play a significant role in the processing of mitochondrial Aβ.…”

Tau and Amyloid- Conformational Change to  -Sheet Structures as Effectors in the Development of Alzheimer's Disease

“…Recently is also suggested the participation of another isomerases like cyclophilin family, but is under research (Koren et al, 2011). In this matter chaperones, specially Hsp90, also can be necessary to maintain Tau in a non-aggregated state, a consequence that may ultimately be deleterious for the brain under pathological conditions (Koren et al, 2009). …”