Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease

This study investigated a library of FDA-approved drugs on Aβ seeding-mediated fibril growth and toxicity. Evidence from genetics, neuropathology, biochemistry and animal models continues to suggest that Aβ aggregation and amyloid formation play central roles in the initiation and progression of neurodegeneration in AD. The nucleated polymerization mechanism is characterized by a nucleation phase associated with the formation of assembly competent oligomers followed by a cooperative oligomer growth and fibril formation by monomer addition. The addition of a small amount of preformed fibrillar aggregates (seeds) eliminates the lag phase of Aβ aggregation and accelerates the fibrillization of monomeric Aβ in vitro and in vivo. Increasing evidence from in vivo studies also suggests that the seeding-mediated aggregation of Aβ proteins is essential for the formation of amyloid plaques, amyloid propagation and spreading via a prion-like mechanism.  Therefore, this study aimed to discover compounds that might interfere with seeding-mediated aggregation and toxicity. Towards this goal, an FDA approved library of bioactive compounds was screened and sixteen molecules were identified as strong inhibitors of Aβ42 seeding-mediated aggregation. Three of these inhibitors, mitoxantrone, bithionol and hexachlorophene,exhibited the strongest inhibition of seeding mediated aggregation and were shown to protect against Aβ-induced neuronal toxicity; these inhibitors were selected for validation in an AD animal model. Herein, these results show that the administration of two of these compounds two months after the initiation of Aβ deposition reduced Aβ accumulation and oligomer formation and protected against Aβ-induced synapse loss and neuronal damage.