Alzheimer’s disease (AD) is a neurological disorder that destroys memory and neurons with high prevalence in the geriatric population. Currently no cure exists to treat AD, but some drugs mitigate the symptoms. AD is manifested by two pathological hallmarks: extracellular amyloid-beta (Aβ) senile plaques and intraneuronal neurofibrillary tangles (NFTs). Aβ-plaques activate microglial cells which in turn increase phosphorylation of tau resulting in hyperphosphorylated of tau (p-tau). NFTs are rich of p-tau, and spatiotemporal distribution coincides with cognitive impairment of AD patients. However, more than half of AD cases have been characterized by the presence of Lewy bodies (LB) and, in many instances, LB disorders have been reported to have concomitant Aβ plaques and NFTs. Our drug discovery program focuses on the synthesis and optimization of multitarget-directed ligands to abrogate aberrant α-syn (responsible of LB formation) and p-tau aggregation and to slow down the progression of AD and related dementias. We synthesized 25 compounds with a triazine-linker and evaluated their effectiveness in reducing protein-aggregation using α-syn. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photo-induced cross-linking of unmodified proteins (PICUP), as well as M17D intracellular inclusion cell-based assays to evaluate the anti-aggregation properties and cellular protection of our best compounds. Best drug candidate was tested on p-tau and disaggregation assays were performed with isolated Aβ-plaques from human AD brains. Our results demonstrated that compound 10 was effective in reducing both α-syn fibrillization and oligomerization in a dose-dependent manner as observed through ThT and PICUP assays. Dose-dependently, Compound 10 was capable of decreasing the inclusion of α-syn M17D neuroblastoma cells. Our hit compound was effective at reducing the formation of recombinant p-tau fibrils by TEM. In contrast to the control (1.5% DMSO), disaggregation experiments showed smaller Aβ-plaques and less paired helical filaments after incubation of 5 days at 37°C with compound 10. The compounds identified here provide molecular scaffolds for further optimization and pre-clinical studies focused on drug development for neurodegenerative diseases.

Triazine-based small molecules for a dual effect on α-synuclein and p-tau aggregation

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