在阿滋海默氏症病理組織切片中，所看到的斑塊沈積，主要為Aβ所構成，是造成阿滋海默氏症神經退化的重要因素。而之前研究指出，Aβ25−35對神經細胞有直接的毒性。到目前為止，Aβ所引起神經細胞死亡的機轉仍待釐清，其中，氧化壓力可能為原因之一。我們培養初生鼠大腦皮質神經細胞，以MTT代謝做存活率分析，來評估Aβ
的毒性。本論文主要是探討抗氧化物質NAC對於Aβ25−35所引起神經細胞死亡的保護作用，發現NAC能對Aβ25−35有神經保護功能，而進一步探究其中機轉為何。在我們的研究中發現，NAC的神經保護作用可能與cdk5有關，同時也發現NAC會增加cdk5的磷酸化，進而推敲其保護機制。在阿滋海默氏症初期，有突觸缺損及神經細胞死亡的現象。文獻指出，Aβ也會參與調控突觸塑性的結構和功能。而PSD-95(post-synaptic density 95) 是一種存在於突觸後神經元細胞質內的蛋白之一，與突觸塑性有著密不可分的關係。在我們的研究得知，Aβ25−35會減低PSD-95而NAC則會逆轉此現象，初步發現這可能也cdk5有關。而在本論文中，我們會更詳細的研究NAC對A25−35所引起的神經細胞死亡機制的探討。

Previous evidence suggests that Amyloid-β peptide (Aβ) plays an important role in neuronal degeneration. The Aβ peptide fragment 25-35
(Aβ 25-35) has been shown to cause direct toxicity to neuron. The precise mechanism by which Aβ induces neuronal apoptosis is still a matter of debate. Moreover, current literature suggests a central role for oxidative stress in AD pathogenesis. We used MTT assay measurement to examine Aβ toxicity in primary culture of rat cortical neurons. This study is to investigate the effect of N-acetylcysteine (NAC), an antioxidant, on Aβ25-35-induced neuronal death. Preliminary result suggested that pretreatment with 10 mM NAC 1 hr before application of Aβ 25 μM prevented the Aβ-mediated cell death. The mechanisms of neuroprotection by NAC in Aβ-induced neuronal death remain incompletely defined. Here, we found that cyclin-dependet kinase 5 (CDK5) may be involved in the mechanism of neuroprotection. Synaptic dysfunction and memory loss is implicated in early-stage Alzheimer’s disease. Recently, it has been shown that a direct role of Aβ in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynptic scaffolding protein that plays a critical role in synaptic plasticity. We found that Aβ reduces PSD-95 protein levels and NAC can reverse the effect. However, the cellular mechanism by which Aβ may affect synapses remains unclear. We will identify the signal cascades underlying the preventive effects of NAC on Aβ-induced neuronal death and synaptic dysfuction.

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