Article

A non-toxic Hsp90 inhibitor protects neurons from Aβ-induced toxicity

Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 05/2007; 17(7):1984-90. DOI: 10.1016/j.bmcl.2007.01.017
Source: PubMed

ABSTRACT The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In Alzheimer's disease, hyperphosphorylation of tau protein results in its dissociation from microtubules and the formation of pathogenic aggregates. An inverse relationship was demonstrated between Hsp90/Hsp70 levels and aggregated tau, suggesting that Hsp90 inhibitors that upregulate these chaperones could provide neuroprotection. We recently identified a small molecule novobiocin analogue, A4 that induces Hsp90 overexpression at low nanomolar concentrations and sought to test its neuroprotective properties. A4 protected neurons against Abeta-induced toxicity at low nanomolar concentrations that paralleled its ability to upregulate Hsp70 expression. A4 exhibited no cytotoxicity in neuronal cells at the highest concentration tested, 10 microM, thus providing a large therapeutic window for neuroprotection. In addition, A4 was transported across BMECs in vitro, suggesting the compound may permeate the blood-brain barrier in vivo. Taken together, these data establish A4, a C-terminal inhibitor of Hsp90, as a potent lead for the development of a novel class of compounds to treat Alzheimer's disease.

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    • "Several groups including ours have reported that low dose 17AAG exerts cell protective effects in different cell types, including NPCs (Ansar et al. 2007, Koga et al. 2006, Wang et al. 2011, Yano et al. 2008). However, no study has been done on whether 17AAG protects cells against stroke related stresses. "
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    • "Similar to Nterminal inhibitors, structural modification of novobiocin has resulted in a class of inhibitors that also promote cytotoxicity (Donnelly and Blagg, 2008; Samadi et al., 2011). However, we have developed a novel class of novobiocin-based C-terminal Hsp90 inhibitors (novologues) which circumvent this issue and exhibit robust neuroprotection of primary neurons in the absence of cytotoxicity (Ansar et al., 2007; Kusuma et al., 2012). KU-32 [N- (7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetra- hydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl) acetamide] is a second generation novologue that also shows efficacy in ameliorating neurodegeneration associated with DPN (diabetic peripheral neuropathy) (Urban et al., 2010, 2012). "
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    ABSTRACT: Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.
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    • "Importantly, KU-32 was found to be minimally cytotoxic to primary cortical neurons and protected against neuronal death induced by amyloid b-peptide (Ansar et al., 2007; Lu et al., 2008). Previous work has suggested that Hsp70 can improve the survival of motor and sensory neurons after axotomy of neonatal sciatic nerves (Tidwell et al., 2004). "
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