Abstract
Alzheimer’s disease (AD) is characterized by memory dysfunction, Aβ plaques together with phosphorylated tau-associated neurofibrillary tangles. Unfortunately, the present existing drugs for AD only offer mild symptomatic cure and have more side effects. As such, developments of effective, nontoxic drugs are immediately required for AD therapy. Present study demonstrates a novel role of Chinese medicine prescription Yuan-Hu Zhi Tong (YZT) in treating AD, and it has substantiated the in vivo effectiveness of YZT in two different transgenic mice models of AD, namely P301S tau and 3XTg-AD mice. Oral treatment of YZT significantly ameliorates motor dysfunction as well as promotes the clearance of aggregated tau in P301S tau mice. YZT improves the cognitive function and reduces the insoluble tau aggregates in 3XTg-AD mice model. Furthermore, YZT decreases the insoluble AT8 positive neuron load in both P301S tau and 3XTg-AD mice. Using microarray and the “Connectivity Map” analysis, we determined the YZT-induced changes in expression of signaling molecules and revealed the potential mechanism of action of YZT. YZT might regulate ubiquitin proteasomal system for the degradation of tau aggregates. The research results show that YZT is a potential drug candidate for the therapy of tau pathogenesis and memory decline in AD.
Highlights
Alzheimer disease (AD) is most vulnerable disease affecting the entire elderly population without curable methods
We found that chronic drug-feed administration of Yuan-Hu Zhi Tong (YZT) (2 or 4 g/kg/d) for nearly 2.5 months until 4.5 months of age, YZT did not substantially alter animal body weight or affect any prominent harmful impacts in P301S tau mice model (Supplementary Figure S1A)
In behavioral studies, we found that YZT administration for 6 months significantly reduced the distance traveled by 3XTg-AD mice to detect the platform during the training in the “Morris Water Maze test (MWM)” (Figure 2E), The transgenic 3XTg-AD vehicle group (Tg-vehicle) took a lengthier route to find the platform compared to vehicle-treated wild-type (WT) mice (Figure 2E)
Summary
Alzheimer disease (AD) is most vulnerable disease affecting the entire elderly population without curable methods. There is a serious demand to develop novel and new drugs targeting the vulnerable neurodegenerative disease including AD. Accumulation of insoluble and toxic protein aggregates and phosphorylated tau species is very rarely researched which is the main cause for the neuron loss with cognitive damages in later AD. Even though AD is commonly believed to be a memory disorder, most people identified with AD create neuropsychiatric symptoms (NPS), such as anxiety, motor impairment, hallucinations, and psychosis, at some stages of their disease. Recent Aβ-based therapies do not prevent cognitive decline, neurofibrillary tangles (NFT) formation or neurodegeneration (Yoshiyama et al, 2013). Recent research have demonstrated a strong correlation between tau pathology, cognitive decline and NPS in the later part of AD (Geerts et al, 2013)
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