Objectives/Goals: Sporadic Alzheimer’s disease (sAD) lacks effective preventive therapies, underscoring the need to target upstream pathogenic drivers. We identified an evolutionarily expanded role for postsynaptic mGluR3 receptors in DLPFC and ERC regions, where they regulate cAMP–calcium-K + channel signaling to sustain neuronal firing and working memory. Methods/Study Population: Here, we employed liquid chromatography–tandem mass spectrometry (LC-MS/MS) to define the proteomic consequences of chronic 2-MPPA treatment in vulnerable (ERC and DLPFC) versus resilient (primary visual cortex) regions. Aberrant calcium signaling, closely linked to neuroinflammation, is an early event in sAD. Aged rhesus macaques, naturally APOE-ε4 homozygotes, show cognitive decline, calcium dysregulation, amyloid deposition, and tau pathology, providing a translational model. mGluR3 signaling is driven by N-acetylaspartylglutamate (NAAG) and constrained by glutamate carboxypeptidase II (GCPII), whose expression rises with age/inflammation and is inhibited by 2-MPPA, providing an opportunity to interrogate unique therapeutic strategies in vulnerable primate cortices. Results/Anticipated Results: We identified >2,400 proteins across experimental conditions, and label-free quantification revealed region-specific differential expression patterns paralleling known vulnerability gradients in sAD. Gene ontology enrichment implicated pathways governing protein deneddylation, amyloid and tau-associated processes, synaptic plasticity, mitochondrial homeostasis, electron transport chain, and oxidative stress, revealing putative targets for therapeutic intervention in sAD. Chronic inhibition of GCPII with oral bioavailable inhibitor 2-MPPA improved task-related neuronal firing critical for higher-order cognition, working memory behavioral performance, and reduced pT217Tau pathology, the most robust biomarker that heralds future neurodegeneration in aged macaques and sAD. Discussion/Significance of Impact: GCPII inhibition activates region-specific molecular programs in the aging primate cortex, protecting circuits vulnerable to sAD. The proteomic signatures reveal candidate biomarkers and targets for preventing calcium-driven degeneration, warranting deeper study of these therapeutic pathways in dementia and neurodegenerative disorders.
Datta et al. (Wed,) studied this question.
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