Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a devastating socio economic 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 multifactoria lnature 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 learningthrough prevention of glutamatergic excitotoxicity triggered by elevated extracellular tonic glutamate levelsleading to activation of extrasynaptic NMDARs (eNMDARs). However, meta-analysis of the memantine's effectsshows that memantine produces modest, short-lived, and highly heterogeneous clinical response. Administeringmemantine at higher concentrations or during the earlier AD stages is not an option because memantine maytrigger serious psychomimetic side effects associated with the block of normal brain activity mediated by synapticNMDARs (sNMDARs). Focusing efforts on drugs that block eNMDARs but not sNMDARs will avoid side effectsassociated 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 andengineered a nanotherapeutic (AuM) that is sufficiently large to be excluded from the synaptic cleft, thus, sparingsNMDARs, but still small enough to efficiently penetrate the brain tissues, reaching and blocking eNMDARs. Wefound that exclusive eNMDAR antagonists provide much stronger neuroprotection than memantine in severalmodels 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 eNMDARantagonist AuM in two complementary AD models: 5X-FAD mice, a model of AD-related amyloid deposition, andP301S tau à ApoE4 homozygous knock-in mice, a tauopathy model. We will compare AuM-treated mice tovehicle-treated mice for disease-relevant read-outs and outcomes, tailored respectively to each model, includingbehavior (memory/learning), accumulation of amyloid plaques or tau tangles, microglial activation/function, CSFbiomarkers, and neuropathology. We also propose to evaluate the feasibility of nose-to-brain delivery of AuMwith the goal of establishing a clinically relevant route for our nanotherapeutic. Specifically, we will determine thetime course of AuM distribution in 5XFAD mice after either direct intra-brain delivery or intranasal administration. The data acquired during this project will allow us to develop the efficient strategy to pursuit of IND-enablingstudies for exclusive antagonists of eNMDARs for treatment of AD. PROJECT NARRATIVE NMDA receptors (NMDARs) are the clinically validated target for Alzheimer's disease (AD), but memantine, an NMDAR antagonist approved by the FDA for moderate-to-severe AD, is not sufficiently efficacious, partly because memantine only acts as a preferential, rather than exclusive, antagonist of the extrasynaptic NMDARs (eNMDARs) that are linked to the activation of multiple pathological signaling pathways in AD. We recently developed a first-in-class exclusive eNMDAR antagonist, which puts us in a unique position to directly examine the molecular and functional impacts of the activity of eNMDARs on multiple aspects of AD-related pathology. Building on our proof-of-concept studies showing that exclusive eNMDAR antagonists can provide neuroprotection in several disease models associated with glutamatergic excitoxicity, we propose to test our exclusive eNMDAR antagonist in two complementary AD mouse models. Our overarching aim is to develop a novel therapeutic for AD patients with minimized side effects and greatly enhanced therapeutic benefits. Intranasal Administration ; Intranasal Drug Administration ; Affect ; Age ; ages ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Amyloid ; Amyloid Substance ; Behavior ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Brain ; Brain Nervous System ; Encephalon ; Clinical Trials ; Corpus striatum structure ; Corpus Striatum ; Striate Body ; Striatum ; striatal ; Amyloid deposition ; Disease ; Disorder ; Drug Design ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Glutamates ; L-Glutamate ; glutamatergic ; Goals ; Gold ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; 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apo epsilon4 ; apoE epsilon 4 ; apoE-4 ; apoE4 ; apolipoprotein E epsilon 4 ; apolipoprotein E4 ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; N-Methyl-D-Aspartate Receptors ; N-Methylaspartate Receptors ; NMDA Receptor-Ionophore Complex ; NMDA Receptors ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Mediating ; Guidelines ; base ; Clinical ; Phase ; Link ; Evaluation ; Failure ; Disease Progression ; Therapeutic ; Amyloid Plaques ; Neuritic Plaques ; amyloid beta plaque ; amyloid-b plaque ; aβ plaques ; cored plaque ; diffuse plaque ; Senile Plaques ; Nature ; cognitive function ; Route ; brain tissue ; extracellular ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; NMDA receptor antagonist ; nerve cell death ; nerve cell loss ; neuron cell death ; neuron cell loss ; neuron death ; neuronal cell death ; neuronal cell loss ; neuronal death ; neuronal loss ; neuron loss ; neuroprotection ; cohort ; Toxicities ; Toxic effect ; novel ; Synaptic Cleft ; Categories ; behavioral test ; behavior test ; disorder model ; Disease model ; Prevention ; Position ; Positioning Attribute ; intervention therapy ; Therapeutic Intervention ; Modeling ; response ; dendrite spine ; Dendritic Spines ; neuropathology ; Meta-Analysis ; tau associated neurodegeneration ; tau associated neurodegenerative process ; tau induced neurodegeneration ; tau mediated neurodegeneration ; tau neurodegenerative disease ; tau neuropathology ; tauopathic neurodegenerative disorder ; tauopathy ; Tauopathies ; Brain region ; therapeutic testing ; therapeutic evaluation ; Causality ; causation ; disease causation ; Etiology ; Apopain ; Apoptosis-Related Cysteine Protease Caspase 3 ; CASP-3 ; CASP3 ; CPP-32 ; CPP32 ; CPP32 protein ; CPP32B ; CPP32beta ; Cysteine Protease CPP32 ; Cysteine Protease CPP32 Gene ; PARP Cleavage Protease ; PARP Cleavage Protease Gene ; SCA-1 ; SCA-1 Gene ; SREBP Cleavage Activity 1 ; SREBP Cleavage Activity 1 Gene ; Yama ; Yama protein ; caspase-3 ; cysteine protease P32 ; CASP3 gene ; Address ; Dose ; Age-Months ; Data ; Apoptotic ; Cellular Stress ; cell stress ; Knock-in Mouse ; KI mice ; knockin mice ; Pathologic ; Molecular ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Pathway interactions ; pathway ; preclinical study ; pre-clinical study ; hyperphosphorylated tau ; hyper-phosphorylated tau ; tau aggregation ; abnormally aggregated tau protein ; filamentous tau inclusion ; microtubule associated protein tau aggregation ; microtubule associated protein tau deposit ; paired helical filament of tau ; self-aggregate tau ; tau PHF ; tau accumulation ; tau aggregate ; tau fibrillization ; tau filament ; tau neurofibrillary tangle ; tau oligomer ; tau paired helical filament ; tau polymerization ; tau-tau interaction ; Ï aggregation ; Neuronal Dysfunction ; neural dysfunction ; nanotherapeutic ; nano therapeutic ; excitotoxicity ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Outcome ; clinically relevant ; clinical relevance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; abeta oligomer ; Amyloid β oligomer ; amyloid beta oligomer ; aβ oligomer ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; FDA approved ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; Inductively Coupled Plasma Mass Spectrometry ; ICP-MS ; power analysis ; preclinical trial ; pre-clinical trial ; Injections ; side effect ; Alzheimer's disease patient ; Alzheimer's patient ; Alzheimer's disease brain ; Alzheimer's brain ;
