PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a devastating socioeconomic impact. The failure rate in AD clinical trials is still ~99%, and the goal of finding efficient drugs that can stop and/or reverse the course of AD remains elusive so far. One of the reasons for these failures is a multifactorial nature of AD which makes it is very challenging to identify the “right” target for efficient therapeutic intervention. NMDA receptors (NMDARs) represent one of just two targets that were clinically validated in AD patients. Therapeutic doses of memantine, an NMDAR antagonist approved by the FDA for treatment of moderate-to- severe AD, were shown to delay the AD progression for 12 weeks and inhibit disruption of spatial learning through prevention of glutamatergic excitotoxicity triggered by elevated extracellular tonic glutamate levels leading to activation of extrasynaptic NMDARs (eNMDARs). However, meta-analysis of the memantine’s effects shows that memantine produces modest, short-lived, and highly heterogeneous clinical response. Administering memantine at higher concentrations or during the earlier AD stages is not an option because memantine may trigger serious psychomimetic side effects associated with the block of normal brain activity mediated by synaptic NMDARs (sNMDARs). Focusing efforts on drugs that block eNMDARs but not sNMDARs will avoid side effects associated with NMDAR antagonists, while producing an enhanced disease-modifying neuroprotective therapy. To address the critical need for exclusive antagonists of eNMDARs, we applied the rational drug design and engineered a nanotherapeutic (AuM) that is sufficiently large to be excluded from the synaptic cleft, thus, sparing sNMDARs, but still small enough to efficiently penetrate the brain tissues, reaching and blocking eNMDARs. We found that exclusive eNMDAR antagonists provide much stronger neuroprotection than memantine in several models associated with glutamatergic excitotoxicity, including protection of dendritic spines from Aβ oligomers. Based upon these exciting results, we propose to conduct an extensive evaluation of our exclusive eNMDAR antagonist AuM in two complementary AD models: 5X-FAD mice, a model of AD-related amyloid deposition, and P301S tau × ApoE4 homozygous knock-in mice, a tauopathy model. We will compare AuM-treated mice to vehicle-treated mice for disease-relevant read-outs and outcomes, tailored respectively to each model, including behavior (memory/learning), accumulation of amyloid plaques or tau tangles, microglial activation/function, CSF biomarkers, and neuropathology. We also propose to evaluate the feasibility of nose-to-brain delivery of AuM with the goal of establishing a clinically relevant route for our nanotherapeutic. Specifically, we will determine the time course of AuM distribution in 5XFAD mice after either direct intra-brain delivery or intranasal administration. The data acquired during this...