阿滋海默症(Alzheimer’s disease)是一種最常見的神經退化性疾病，臨床上主要具備 兩種病理特徵，包括在神經細胞外由 Aβ 所聚而成的類澱粉(amyloid plaques)及在細胞 內由過度磷酸化的 tau 所組成神經纖維糾結(neurofibrillary tangles)等。越來越多的證據 指出阿滋海默症基本上是屬於代謝疾病，事實上臨床與實驗上的結果皆顯示阿滋海默 症腦部的神經細胞其胰島素及第一型類胰島素生長因子的訊息傳遞均有不正常受到抑 制的情形，這些結果顯示了胰島素及第一型類胰島素生長因子的訊息抵抗可能是連結 代謝症候群與阿滋海默症兩者間的共同分子機轉，然而胰島素及第一型類胰島素生長 因子的訊息傳遞與 Aβ 造成神經退化之間的確切關聯則不是非常清楚。在我們實驗室初 步的結果顯示，一種負責調控細胞內能量平衡的蛋白質腺苷單磷酸活化激酶(AMPK)， 可能透過參與神經細胞內的胰島素及第一型類胰島素生長因子的訊息傳遞途徑來緩解 Aβ 所造成之神經毒性。除此之外，Aβ 也會透過干擾 PI3k/Akt 的活性，抑制細胞內 AMPK 活化並造成 tau 過度磷酸化。根據這些發現，我們假設 AD 的病人其胰島素及第一型類 胰島素生長因子訊息傳遞若發生抵抗的現象，便會導致神經退化的情形發生。為了證 明此觀點，本計畫預計將實驗設計分為下列三項來進行討論：(i)首先我們預計先透過 各種不細胞實驗模式，釐清胰島素及第一型類胰島素生長因子訊息傳遞與 Aβ 造成神經 毒性之間的因果關係 (ii)其次，我們將透過進行三項不同的動物實驗模式，來驗證先前 實驗的觀察結論 (iii)最後，我們會去探討神經細胞老化過程與胰島素及第一型類胰島 素生長因子訊息傳遞之間的關係，並嘗試在老化過程中是否能透過調控胰島素及第一 型類胰島素生長因子訊息傳遞活性來對抗 Aβ 所造成神經毒性。總合來說，透過執行本 計畫我們將釐清胰島素及第一型類胰島素生長因子訊息傳遞路徑與 Aβ 所造成神經退 化之兩者間的關係，我們希望透過執行本計畫以瞭解神經細胞內胰島素及第一型類胰 島素生長因子訊息傳遞的詳細分子機轉，並有助於在未來開發出更有效的阿滋海默症 治療策略與藥物。 Alzheimer’s disease (AD) is the most common neurodegenerative disease. It is characterized by two diagnostic pathological hallmarks like amyloid plaques (APs) which are mainly formed by Aβ peptides accumulation, and neurofibrillary tangles (NFTs) which are composed of hyperphosphorylated tau protein. Growing evidence supports the concept that AD is fundamentally a metabolic disease. In fact, both clinical and experimental data demonstrated insulin and insulin-like growth factor-1 (IGF-1) signaling was aberrantly distributed in AD neurons. Consequently, neuronal resistance for insulin/IGF-1 signaling might represent a molecular link between metabolic syndrome and AD. However, the mechanism how insulin/IGF-1 signaling influences the onset and progression of Aβ-induced neurodegeneration remain incompletely understood. As the results, the present study will try to demonstrate a possible mechanism of neuronal insulin/IGF-1 resistance in Aβ-induced neurotoxicity. Our preliminary data indicated that AMP-activated protein kinase (AMPK), a cell energy sensor that activated by insulin/IGF-1 signaling could alleviate Aβ-induced neurotoxicity. Moreover, Aβ inhibit neuronal insulin-stimulated signals by interfering with PI3k/Akt, which leads to impaired AMPK activation and responsible for the hyperphosphorylation of tau. Based on these findings, we postulated that AD neurons degeneration was caused by impairments in brain insulin/IGF-1 signaling and insulin/IGF-1 resistance. To confirm this hypothesis, our experimental designs of this project will be divided into three parts to discuss: (i) Firstly, we will investigate the interrelationship between impaired insulin/IGF-1 signaling and Aβ neurotoxicity by several in vitro model. (ii) To evaluate the interrelationship between impaired insulin/IGF-1 signaling and Aβ neurotoxicity, three animal models will be applied. (3) To elucidate whether the aging process is associated with brain insulin and insulin-like growth factor 1 (IGF-1) resistance. In conclusion, we will determine the effects and the possible mechanisms involving modulation of insulin/IGF-1 signaling and Aβ-related neurodegeneration. We expect our results can be a contribution to the of the understanding mechanisms involved in neuronal insulin/IGF-1 signaling, and shed light onto possible therapeutic approaches to provide new AD therapeutic strategies and drug targets in future.
