The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer’s Disease

Functional changes in chaperone systems play a major role the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While may occur naturally with age or stress trauma, mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads hyperphosphorylation tau by Hsp90-dependent process triggers neurofibrillary tangle neurotoxicity. Several co-chaperones Hsp90 can influence phosphorylation tau, including FKBP51, FKBP52 PP5. In particular, elevated levels FKBP51 are further AD. Recently, dihydropyridine LA1011 was shown reduce pathology amyloid transgenic AD mice, probably through its interaction Hsp90, although precise mode action is currently unknown. Here, we present co-crystal structure complex fragment Hsp90. We show disrupt binding which might help rebalance Hsp90-FKBP51 machinery provide favourable prognosis towards However, without direct evidence, cannot completely rule out effects on other Hsp90-co-chaprone complexes they in, client proteins. Nonetheless, it highly significant showed promise our previous mouse models, generally affecting older patients, where slowing progression could result no longer being life limiting. clinical value possible derivatives thereof remains be seen.