Abstract
Alzheimer's disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of beta-amyloid (A beta) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. A beta oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the de. ning pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Ab toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to A beta peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against A beta-induced cell death; the potential toxicity of each agent alone was also determined. The data indicated that several of the compounds decreased Ab toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against A beta. The novobiocin analogues alone were not toxic even up to 10 mu M concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 mu M, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs. (C) 2008 Elsevier Ltd. All rights reserved.