Treating Pathological Tau Aggregates by Inhibiting the HSP90 Activator AHA1

Competitive Advantages

  •     Targets underlying pathology of Alzheimer’s disease and other tauopathies
  •     Cell studies show inhibition of Hsp 90 co-factor Aha1 reduces tau aggregation
  •     HSP90 and its co-factors provide novel drug target for future research

Summary

Pathogenic tau aggregation is one of the major hallmarks associated with Alzheimer’s disease and a number of other tauopathies. The microtubule‑associated protein tau forms neurotoxic aggregates that promote cognitive deficits in tauopathies. The 90 kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood‑brain barrier permeable and many present associated toxicities.

USF researchers have validated that the Hsp90 cofactor Aha-1 colocalized with tau to promote fibrilization and synergizes to form tau aggregates. Further, Aha1 overexpression leaders to increased insoluble and oligomeric tau species and cognitive impairments in mice.

USF researchers have discovered a treatment for the effective inhibition of the Hsp90 cofactor Aha-1 via a small molecule inhibitor delivered by retro-orbital injections. This treatment has the potential to significantly reduce tau levels and may ultimately reduce neuronal loss and cognitive decline that is associated with Aha-1 over-expression. This method of inhibiting the HSP90 system and its co-factors presents a valuable target for the treatment of Alzheimer’s disease and other tauopathies, and is the subject of ongoing behavioral studies by USF researchers.

Hsp90 and Aha1 synergize to form tau aggregates. (A) Recombinant P301L tau fibril formation measured by Thioflavin T (ThT) fluorescence over a period of 72 h with or without the addition of Hsp90 and Aha1 (results represent the mean ± SEM, n = 3). B Representative 20,000× TEM images of end product from (B). Scale bar represents 2 μm.

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Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date
The Hsp90 Activator Aha1 Drives Production of Pathological Tau Aggregates Nationalized PCT United States 16/486,975 11,318,155 2/23/2018 5/3/2022 4/17/2038