## 2 Immunomodulatory Function of Extracellular Hsp60, Hsp70, and Hsp90
### Alzheimer's Disease  
AD is a neurodegenerative disorder in which the amyloid-\(\beta\) peptide (A\(\beta\)) accumulates in extracellular deposits named plaque, whereas neurofibrillary tangles (NFTs) occur intracellularly with hyperphosphorylated tau [12; 58]. Under pro-aggregating conditions (37 \({}^{\circ}\)C and stirring), extracellular Hsp60 inhibits the onset of A\(\beta\) cross-\(\beta\)-structure formation that typically accompanies the peptide assembly toward higher ordered structures [59]. The hypotheses formulated on the possible role of Hsp60 in the formation of protein deposits are mainly based on its holding activity. For instance, Hsp60 could act as a noncatalytic inhibitor of polypeptide aggregation by sequestering unfolded monomers via hydrophobic interactions. However, the stoichiometric ratio of the A\(\beta\)peptide/Hsp60 and the limitation of the methods applied for these measurements put a question mark on the validity of the results. In fact, the inhibition of amyloid formation appears discontinuous when passing from a 75:1 to 50:1 molar ratio. Furthermore, the method used, size-exclusion chromatography, cannot distinguish between A\(\beta\) monomers or peptide oligomers of very low molecular weight, such as dimers or trimers, nor can it discriminate between on- pathway and off-pathway species. These data suggest that Hsp60 exerts its inhibitory action only under stress conditions and, in particular, in the presence of other factors such as high temperature and stirring, which favor the formation of on-pathway seeding species. [59]. Higher levels of Hsp60 were found in lymphocytes isolated from AD subjects [60; 61]. \(\alpha\beta\) immunization with peptides derived from Hsp60 induced a decrease of cerebral amyloid burden in a mouse model [62]. Like Hsp60, extracellular Hsp70 also interacts with A\(\beta\) oligomers, blocking their oligomerization into fibers and reducing their toxicity [63]. The engineered form of secreted Hsp70 (secHsp70) in _Drosophila_ protects against the toxicity induced by A\(\beta\)42 deposits in the extracellular milieu [64]. Exogenous Hsp90 was found to induce microglial activation and to facilitate phagocytosis and clearance of A\(\beta\) directly  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Disease** & **Hsp60** & **Hsp70** & **Hsp90** \\ \hline
**Alzheimer’s disease (AD)** & Anti- & Anti- & Pro- \\
**Parkinson’s disease (PD)** & Anti- & Anti- & Pro- \\
**Huntington’s disease (HD)** & Anti- & Anti- & Pro- \\
**Amyotrophic lateral sclerosis (ALS)** & Not reported & Anti- & Not reported \\
**Multiple sclerosis (MS)** & Pro- & Pro- & Pro- \\ \hline \hline \end{tabular}
\end{table}
Table 1: Anti- and proinflammatory effects of extracellular Hsp60, Hsp70, and Hsp90 in neurodegenerative diseases.  
via the TLR4 pathway, but when bound to the A\(\beta\) oligomers, it induced the production of IL-6 and TNF-\(\alpha\)[65]. In another work, it was revealed that Hsp90 modulates the formation of the STIP1 (or Hsp70/Hsp90 organizing protein (HOP))/PrPC complex, which inhibits the neuroprotective role of STIP1 against amyloid-beta peptide [66]. However, it is still unclear whether extracellular Hsp70/Hsp90/STIP1 in AD brain exists separately or as a complex with the A\(\beta\) aggregate [66]. All these observations indicate that the understanding of Hsp90's role in neurodegeneration deserves further investigation.