Research Projects

Background and Rationale: Tau is a microtubule-associated protein critical for stabilizing microtubules and transporting mitochondria, vesicles, and neurotransmitters in neurons. In Alzheimer’s disease (AD), post-translational modifications, especially hyperphosphorylation and acetylation, lead to tau detachment and aggregation into neurofibrillary tangles (NFTs), triggering inflammation, synaptic dysfunction, and neuronal death. While tau hyperphosphorylation is well studied, tau acetylation is now recognized as a key factor in promoting tau aggregation and neurotoxicity. It is regulated by acetyltransferases like p300/CBP and deacetylases such as HDACs and sirtuins (SIRTs). Reduced SIRT activity in aging and AD is linked to increased tau acetylation, impaired protein clearance, and synaptic loss. SIRT-mediated deacetylation promotes tau degradation via autophagy and the ubiquitin-proteasome pathway, supporting its therapeutic relevance. Therapeutic Potential of Natural Compounds: Natural compounds like curcumin, apigenin, and resveratrol have shown SIRT activation but suffer from poor bioavailability and multiple off-target effects. In contrast, citrus flavones Nobiletin and Tangeretin (NOB/TAN) possess better bioavailability, blood-brain barrier permeability, and neuroprotective potential. NOB/TAN have been shown to activate SIRTs, reduce tau phosphorylation, modulate oxidative stress, and improve cholinergic signalling. Preliminary Work: We extracted and characterized citrus peel extract enriched in NOB/TAN and confirmed their antioxidant and anti-inflammatory properties in vitro. SH-SY5Y neuronal cells were used to assess cytotoxicity via MTT assay. An in vitro AD model was established using okadaic acid (OA), which induces tau hyperphosphorylation. To study tau acetylation, cells were transfected with K174-acetylated tau mimic constructs. Preliminary results showed that K174-acetylation impaired autophagy and neuronal function. Treatment with NOB/TAN reduced tau acetylation and partially restored cellular homeostasis, supporting their role in modulating tau pathology. Research Gap: Despite growing interest, the effects of tau acetylation on autophagy, mitochondrial function, and synaptic signaling remain underexplored. The molecular pathways through which NOB/TAN influence tau acetylation and neuronal health, especially in vivo, are not yet fully defined. Understanding these interactions may offer new therapeutic insights. Aim of the Study: To investigate the potential of NOB/TAN in modulating tau acetylation and related synaptic dysfunctions in AD, using in vitro and in vivo models focused on tau aggregation, autophagy, and synaptic integrity.