Methanol extract from miracle fruit seeds mitigates Alzheimer's disease and enhance autophagy via suppressing the AKT/mTOR signal pathway

<b>Background:</b> Alzheimer's disease (AD) is a neurodegenerative disease. In previous study, we discovered that methanol extract of miracle fruits seeds (MFSs) had a therapeutic effect on AD model mice. <b>Objective:</b> In this research, we aimed to study the role of MFSs in alleviating amyloid-β (Aβ) deposition and further explore the possible mechanism of action of MFSs. <b>Methods:</b> We used behavioral tests and various immunolabeling techniques on two AD model (Aβ transgenic model strain CL4176 of Caenorhabditis elegans and the 3 × Tg-AD mice). <b>Results:</b> In CL4176, MFSs (10 μg/mL) could effectively alleviate the paralysis caused by Aβ, the Aβ plaques were significantly reduced, the transcription levels of <i>Aβ</i>, <i>age-1</i>, <i>akt-1</i> and <i>mTOR</i> genes were significantly downregulated, and the transcription of autophagy-related gene <i>lgg-1</i> was enhanced. The cognitive function of mice in the MFSs group was improved, which was related to reduced synapse loss and Aβ-positive neurons in the brain. Meanwhile, the transcription levels of <i>amyloid-β protein precursor (AβPP)</i>, <i>Tau</i>, <i>Akt</i> and <i>mTOR</i> were significantly reduced. The protein expressions of PSD95, SYN1, LC3II/I and Beclin-1 were significantly increased, and the value of p62/SQSTM1, p-AKT/AKT, p-mTOR/mTOR were reduced. <b>Conclusions:</b> MFSs significantly alleviates Aβ deposition in CL4176 and mice. The mechanism by which it improves cognitive function in AD mice may be related to enhanced autophagy regulated by the Akt/mTOR signaling pathway.