| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學系 === 104 === Alzheimer’s disease (AD), one of the most common neurodegenerative diseases, leads to memory impairment and other cognitive problems. The two pathological hallmarks of AD are accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, by which they associate with synapse loss and neuronal death. Recent studies have indicated that Aβ-induced glutamate neurotransmission may play a crucial role in AD. A rise in glutamate could result in over-stimulating synaptic glutamate receptors such as AMPAR, NMDAR, Kainate receptor, and mGluR1/3/5, and subsequently cause neuronal cell death. The clinical use of memantine, an uncompetitive N-methyl-D-aspartate (NMDA) antagonist, strengthens this opinion. In this study, we screened Chinese herbal medicines/herbal extracts for ameliorating the Aβ-induced pathophysiological neurotransmission. We established the primary culture of cortical neurons isolated from postnatal 1-3 days mice. These neurons have been characterized by markers of glutamatergic neurons and neuronal networks such as vGLUT1/2, AMPAR, NMDAR, PSD95, type III tubulin. After stimulating by oligomeric forms of Aβ 1-42, these neurons depolarize, indicating by a slow response voltage sensitive dye DiBAC4(3). Utilizing this platform, we found 6 out of 16 herbal extracts which are effective to alleviate Aβ-induced abnormal depolarization and temporarily named two of them P1029 and P1033. We also eventually found a pure compound, P1033-BE, is capable to block Aβ-induced abnormal depolarization. Using agonists and antagonists of glutamatergic receptors, we dissect that the effect of P1033-BE could mediate through NMDAR and AMPAR. The molecular mechanisms of this effective pure compound on which pathways are being explored. Hopefully, we will make this ultimately become clinical drugs to treat AD patients.
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