The dihydropyridine LA1011 modulates multiple Hsp90—co-chaperone interactions relevant to Alzheimer’s disease

Abstract

LA1011 (dimethyl 4-(4-Trifluoro-methyl-phenyl)-2,6-bis(2-dimethylamino-ethyl)-1-methyl-1-4 dihydropyridine-3-5-dicarboxylate dihydrochloride) has been shown to improve the prognosis of Alzheimer’s disease (AD) in an APPxPS1 mouse model. The target for LA1011 is the C-terminal domain of Hsp90, where it was shown previously to reduce the interaction between FKBP51 and Hsp90. FKBP51 is a Hsp90 co-chaperone that promotes the trans to cis isomerization of proline at multiple tau pSer/pThr-pro sites, thus preventing their dephosphorylation. Potentially this leads to the hyperphosphorylation of tau and the formation of neurofibrillary tangles that eventually lead to the development of AD. In this study, we demonstrate that LA1011 affects the FKBP51-mediated regulation of Hsp90 but also potentially modulates the regulation Hsp90 by the co-chaperones FKBP52, CHIP, Aha1, Hch1 and PP5. We also show that the co-chaperones HOP, CDC37 and Sgt1 appear to enhance mildly the binding of LA1011. In contrast, nucleotide alone or nucleotide with Aha1 or p23, which promote the closed conformation of Hsp90, reduce the affinity for LA1011. We conclude that LA1011 can modulate the regulatory landscape of the Hsp90 co-chaperone network, which in turn appears to improve the prognosis of Alzheimer’s disease.

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ORCID for Matthias Baud: orcid.org/0000-0003-3714-4350

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