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Review
. 2018 Sep 1;19(9):2603.
doi: 10.3390/ijms19092603.

Heat Shock Proteins in Alzheimer's Disease: Role and Targeting

Claudia Campanella  1 , Andrea Pace  2 , Celeste Caruso Bavisotto  3 , Paola Marzullo  4 , Antonella Marino Gammazza  5 , Silvestre Buscemi  6 , Antonio Palumbo Piccionello  7
Affiliations
Review

Heat Shock Proteins in Alzheimer's Disease: Role and Targeting

Claudia Campanella et al. Int J Mol Sci. .

Abstract

Among diseases whose cure is still far from being discovered, Alzheimer's disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

Keywords: Alzheimer’s disease; Hsp60; Hsp70; Hsp90; amyloid peptide; chaperones; heat shock proteins; protein Tau.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hsp60 and Alzheimer’s disease. Oxidative stress may cause Hsp60 structure modifications leading to loss of Hsp60 functions with the consequences of protein misfolding, aggregation and deposition.
Figure 2
Figure 2
Chemical structures of Hsp60 inhibitors binding the ATP binding site.
Figure 3
Figure 3
Chemical structures of Hsp60 inhibitors binding the Cys442 residues.
Figure 4
Figure 4
Chemical structures of Hsp60 modulators.
Figure 5
Figure 5
Chemical structures of Hsp70 inhibitors targeting the ATP binding site.
Figure 6
Figure 6
Chemical structures of modulators of Hsp70 expression.
Figure 7
Figure 7
Hsp90 inhibition in Alzheimer’s disease. Hsp90 down regulation may induce the reduction of Tau hyperphosphorilation and aggregation and may trigger the so-called stress response. In fact, in the presence of cellular stress and Hsp90 inhibitors, Heat Shock Factor 1 (HSF-1) dissociates from the chaperone, reaches the nucleus, inducing the activation of heat shock genes and of the stress response via the production of Hsp90, Hsp70 and Hsp40, restoring protein homeostasis.
Figure 8
Figure 8
Chemical structures of Hsp90 inhibitors targeting the ATP binding site.
Figure 9
Figure 9
Chemical structures of Hsp90 inhibitors binding the C-terminal domain.
Figure 10
Figure 10
Chemical structures of Hsp90 inhibitors/modulators.
See this image and copyright information in PMC

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