2026-10-09T08:43:40Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34001199 2026-09-29T02:13:38Z category_25195 portal_959 item_type_8 month_year_09_2026

Understanding the Tau-PSD-95 Binding Interface: A Pathway to Small Molecule Therapeutics for Alzheimer's Disease Carmen Rozelda Campisi (25112094) Proteins and peptides Alzheimer's Disease Tau PSD-95 Molecular modelling Protein-protein interactions Protein-peptide docking Alanine scanning Binding site Excitotoxicity Neurotoxicity <p dir="ltr">Alzheimer’s disease (AD) is a progressive neurodegenerative condition responsible for 60–80% of dementia cases. 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. This study addresses these challenges with a chemistry-based approach, using solid-phase peptide synthesis (SPPS) with alanine scanning to identify the crucial amino acids involved in the binding between tau and PSD-95. Binding interactions were measured using protein interface-catalysed capture (PICC) analysis, and fluorescence polarisation (FP) assays were conducted to test proof-of-principle binding affinities for future alanine-scanning analysis and drug targets. In this study, PICC analysis established critical binding residues within the tau R2 and P2 domains. Additionally, FP assays supported the evidence of binding within the R2, P1, and P2 tau domains.</p><p dir="ltr">This research holds promise for resolving the structure of intrinsically disordered proteins and pinpointing specific molecular sites for the development of inhibitory drugs aimed at preventing excitotoxic pathology in AD patients, thereby reducing the risk of neurodegeneration and offering potential therapeutic interventions for AD.</p> 2026-09-29T02:13:38Z Text Thesis 10.25949/34001199.v1 https://figshare.com/articles/thesis/Understanding_the_Tau-PSD-95_Binding_Interface_A_Pathway_to_Small_Molecule_Therapeutics_for_Alzheimer_s_Disease/34001199 In Copyright