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- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

1

Heat shock proteins and chaperones are elevated in Alzheimer's brain. (A) Brain tissue from medial temporal gyrus of two Alzheimer's disease (AD) patients and two age/gender-matched controls were homogenised and analysed by Western blot. Chaperone proteins were dramatically elevated in AD brain compared with control. ptau antibody recognising tau phosphorylated at pS212 was used to confirm pathology. GAPDH levels were unchanged. (B) Brain sections from rTg4510 transgenic mice that have inducible P301L human tau expression in the forebrain and non-transgenic littermates were stained with an anti-Hsp27 antibody. Dramatic gliosis was evident throughout the CA1 and caudate putamen and along the alveus in transgenic mice compared with control.

2

Role of chaperones and HSF1 in the processing of Aβ: a cycle of toxic soluble intermediates? Following a stress stimulus, HSF1 is phosphorylated by the stress-activated protein kinase cascade in the cytosol. HSF1 free of Hsp90 binding then trimerises and enters the nucleus, producing de novo copies of heat shock protein and APP mRNA. The HSPS shepherd APP to its destination and more Aβ is released. Extracellular chaperones prevent amyloid plaque formation and preserve soluble toxic amyloid species 90 (oligomers), leading to a stress loop. Intracellular Aβ may facilitate this stress and even further it. Hsp90 inhibition may compound the problem by indirectly allowing more HSF1 to become active.

3

Current model of tau processing through the chaperone network. Kinases such as MARK2 and Akt appear to operate in concert with Hsp90 to affect phosphorylation. MARK2 and Akt synergise to phosphorylate tau at KXGS motifs, which prevents tau degradation by the chaperone system. Other aberrant or misfolded tau is recognised by the Hsp40/Hsp70 complex. From here, tau can be either directly degraded by this complex or passed to Hsp90 to form an intermediate Hsp90 complex. Akt is associated with this complex. Here several courses can be taken based on the context: The Hsp90 complex can mature into a refolding machine and repair tau, or tau degradation can be facilitated, either out of necessity or Hsp90 inhibition. When Akt is present, tau degradation is impaired and thus it accumulates; however, when Akt is reduced by siRNA, tau degradation is enhanced. Akt is also a client of Hsp90 and thus is degraded in a fashion similar to tau.