The potential of mulberry (Morus alba L.) leaf extract against pro-aggregant tau-mediated inflammation and mitochondrial dysfunction

In Alzheimer's disease (AD), Tau aggregates trigger microglial activation to release inflammatory factors and cause mitochondrial dysfunction, oxidative stress, and neuronal damage. With abundant potent antioxidants, mulberry (Morus alba L.) leaf extract has the potential to treat diseases associated with neuroinflammation, mitochondrial dysfunction, and oxidative stress. This study examined the neuroprotective effects of a mulberry leaf extract against pro-aggregant Tau-mediated inflammation and mitochondrial dysfunction in SH-SY5Y cells expressing the ΔK280 Tau repeat domain (Tau_RD). His-tagged ΔK280 Tau_RD fibrils prepared from E. coli activated BV-2 microglia, as revealed by their altered morphology, increased nitric oxide production, and elevated ionized calcium binding adaptor molecule 1 (IBA1) and major histocompatibility complex 2 (MHCII) expression. The mulberry leaf extract suppressed the production of pro-inflammatory mediators, including NO, IL-1β, IL-6, and TNF-α, and the expression of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 (CASP1) in ΔK280 Tau_RD fibril-stimulated BV-2 cells. Application of conditioned media collected from ΔK280 Tau_RD fibril-activated BV-2 cells induced cellular inflammation in ΔK280 Tau_RD-DsRed-expressing SH-SY5Y cells. The mulberry leaf extract protected these cells by suppressing lactate dehydrogenase (LDH) release, caspase-3 activity, NLR family pyrin domain-containing 1 (NLRP1), CASP1, IL-1β, IL-6, TNF-α, and reactive oxygen species as well as by enhancing neurite outgrowth. In addition, mulberry leaf extract increased mitochondrial membrane potential, lowered mitochondrial superoxide levels, and increased superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and nuclear factor erythroid 2-related factor 2 (NRF2) levels in SH-SY5Y cells. In conclusion, mulberry leaf extract displayed neuroprotective effects by exerting anti-inflammatory and antioxidative activities to ameliorate pathological Tau-mediated mitochondrial dysfunction in a human Tau cell model. The results of this study support the notion that the mulberry leaf extract is a potential disease-modifying therapeutic agent for AD.