Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy.

Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

Amyloid-ß oligomer targeted theranostic probes for in vivo NIR imaging and inhibition of self-aggregation and amyloid-ß induced ROS generation.

To enable the early detection and intervention of Alzheimer's disease (AD), it is highly desirable to develop novel theranostic agents for simultaneous detection of toxic and pathogenic amyloid-ß (Aß) oligomers in vivo and attenuation of Aß-induced toxicity. Herein, we report a new series of oligomeric Aß targeted near infrared (NIR) emissive dibutylnaphthylamine-based cyanine probes for in vivo and ex vivo imaging of Aß in AD mouse model. These new fluorophores exhibited strong solvatochromism and a large bathochromic shift of the emission spectrum upon binding with Aß species, giving rise to advantageous NIR emission. Besides, they showed an intriguingly stronger fluorescence enhancement upon interacting with Aß oligomers and monomers, and binding affinity toward Aß oligomers and monomers than Aß fibrils, suggesting they were selective to Aß oligomers and monomers. In addition to low toxicity, one of the fluorophores, DBAN-SLM, showed remarkably effective inhibitory effect on Aß aggregation, significant neuroprotection effect against the Aß-induced toxicities, and suppression on Aß-induced reactive oxygen species (ROS) generation. Because of excellent blood-brain barrier (BBB) permeability, good biocompatibility and stability, high specificity towards Aß oligomers as well as strong turn-on fluorescence upon Aß binding, DBAN-SLM was successfully applied for in vivo and ex vivo imaging of Aß in AD mouse model, signifying its great promise as a useful theranostic agent for the early diagnosis and therapy of AD. Our results also demonstrated for the first time that the dibutyl-2-naphthylamine moiety is a useful and effective structural building block to promote the targeting capability of oligomeric Aß.

Qingyangshen mitigates amyloid-ß and Tau aggregate defects involving PPARα-TFEB activation in transgenic mice of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid ß plaques (Aß) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology. PURPOSE: The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation. METHODS: QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro. RESULTS: Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aß and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro. CONCLUSION: QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery.

NeuroDefend, a novel Chinese medicine, attenuates amyloid-ß and tau pathology in experimental Alzheimer's disease models.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-ß (Aß) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid ß (Aß) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-ß/α), Aß and 4G8 positive Aß burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans.