Understanding the Tau-PSD-95 Binding Interface: A Pathway to Small Molecule Therapeutics for Alzheimer's Disease

With no current cure, AD is quickly becoming one of the most lethal and burdensome diseases of the 21st century. Although key biological hallmarks (amyloid-beta plaques and neurofibrillary tangles) have been identified at the end stages of disease, the pathogenesis of AD is not well understood.</p><p dir="ltr">In AD conditions, the microtubule-associated protein tau has been found to mislocalise from the axon to the somatodendritic compartment of neurons, leading to atypical cellular interactions.

Current research has identified that interactions between the proteins tau and post-synaptic density 95 (PSD-95) can occur at the post-synapse within this pathological context. This interaction results in excitotoxicity driven by the overactivity of N-methyl-D-aspartate receptors (NMDARs), ultimately leading to cell death. Disrupting the tau-PSD-95 interaction using small molecule inhibitors could potentially prevent irreversible damage in the early stages of AD.</p><p dir="ltr">Due to the intrinsically disordered nature of the tau protein, identifying target areas for therapeutics poses a challenge that traditional methods like X-ray crystallography cannot overcome.