In the brain of Alzheimer’s disease (AD) patients, accumulation of amyloid-β and tau is accompanied by synaptic and neuronal loss and chronic inflammation. Amyloid-β is generated from the processing of the amyloid precursor protein (APP), through sequential cleavage by the β-APP-cleaving enzyme (BACE1) and the γ-secretase. The BACE1 promoter contains consensus binding sites for transcription factors, including the Peroxisome Proliferator-activated receptor-γ (PPAR- γ). PPAR- γ is a nuclear receptor, which upon ligand activation can regulate the transcription of target genes. Therefore, manipulation of PPAR-γ activity may present a potential avenue for targeting AD pathology. Nuclear receptor co-repressor 1 (NCoR) is a co-repressor of PPAR-γ, amongst other transcription factors, and exerts its repressive function by working with histone deacetylase 3 (HDAC3). We hypothesised that NCoR drives production of amyloid-β in AD through PPAR-γ modulation and our aim was to investigate the mechanisms whereby NCoR affects amyloid-β generation and degradation in the N2a neuroblastoma cell line. In addition, we assessed whether HDAC3 inhibition resulted in the opposite effects, and also affected synaptic and inflammatory markers in an ex vivo AD model. We have shown that NCoR is enriched in neurons and certain glial cells, that its expression is increased in the hippocampus of AD patients compared with healthy controls, and that NCoR increases with age. In addition, NCoR over-expression in N2a cells resulted in increased BACE1 expression, while it led to a reduction in the levels of APP and amyloid-β. Conversely, inhibition of HDAC3, using a specific inhibitor, resulted in elevations of APP and amyloid-β levels. Furthermore, HDAC3 inhibition in organotypic brain cultures of 5xFAD mice increased APP expression, lowered glial activation and rescued spine density, without altering amyloid-β levels. These data suggest that NCoR and HDAC3 play multi-faceted roles in the modulation of AD pathology, most prominently on the expression of APP, and that targeting the NCoR/HDAC3 complex could be a promising therapeutic strategy for AD.