Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy‐lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta‐amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg‐AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C‐terminal fragments (CTF‐β/α), β‐amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Alzheimer’s disease (AD) is a degenerative disorder typified by progressive deterioration of memory and the appearance of β-amyloid peptide (Aβ)-rich senile plaques. Recently we have identified a novel function of a patented formulation of modified Huanglian-Jie-Tu-Tang (HLJDT-M), a Chinese herbal medicine, in treating AD in in vitro studies (US patent No. 9,375,457). HLJDT-M is a formulation composed of Rhizoma Coptitis, Cortex Phellodendri and Fructus Gardeniae without Radix Scutellariae. Here, we assessed the efficacy of HLJDT-M on a triple transgenic mouse model of AD (3XTg-AD). Oral administration of HLJDT-M ameliorated the cognitive dysfunction of 3XTg-AD mice and lessened the plaque burden. In addition, biochemical assays revealed a significant decrease in levels of detergent-soluble and acid-soluble Aβ via decreasing the levels of full length amyloid-β precursor protein (FL-APP) and C-terminal fragments of APP (CTFs) in brain lysates of HLJDT-M-treated mice. HLJDT-M treatment also significantly reduced the levels of FL-APP and CTFs in N2a/SweAPP cells. In contrast, treatment using the classical formula HLJDT did not reduce the memory impairment of 3XTg-AD mice and, rather, increased the Aβ/Fl-APP/CTFs in both animal and cell culture studies. Altogether, our study indicates that HLJDT-M is a promising herbal formulation to prevent and/or cure AD.

Ppardδ, one of the lipid-activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism regulating the function of antigen-presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c + cells in atherosclerosis. We used the Cre-loxP approach to make conditional deletion of Ppard in CD11c + cells in mice on Apoe -/background, which were fed with high cholesterol diet to develop atherosclerosis.Ppard deficiency in CD11c + cells attenuated atherosclerotic plaque formation and infiltration of myeloid-derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe -/mice.These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis. K E Y W O R D S atherosclerosis, dendritic cells, inflammation, PPARdelta