PS128精神益生菌對於阿茲海默氏症小鼠模式的效益及其作用機制

Abstract

隨著高齡社會的到來，失智症人數急遽增加，其中阿茲海默氏症是失智症中最常見的類型。大量的β類澱粉蛋白質(Aβ)與Tau蛋白質過度磷酸化堆積是阿茲海默氏症最主要的病理特徵，然而目前不論針對Aβ或是tau的處理仍無法有效治療方式；因此迫切需要開發新的治療策略以因應當前全球最棘手的阿茲海默氏症。依據腸腦(gut-brain axis)雙向影響的原理，先前研究發現口服益生菌可避免或是延緩因壓力或是腦室急性注射Aβ的方式造成認知功能的受損；然而其所使用的動物模式，都無法代表典型的阿茲海默氏症動物模式。另外，台灣本土發現的PS128精神益生菌可以減少因壓力產生的焦慮、憂鬱與周邊發炎反應等正向效果。因此本研究將使用偶發型與家族型兩種阿茲海默氏症動物模式探討PS128精神益生菌於認知功能的成效，進而探討其作用的分子機制。本研究將用6個月大的3×Tg-AD (三基因轉殖鼠)與C57BL/6J公鼠於側腦室急性注射STZ 4 μl (Streptozotocin; 鏈脲黴素)或是生理食鹽水，注射前7天起小鼠接受每天管餵一次PS128 100 μl (10^10 CFU/ml)或vehicle處理，連續給予33天。首先，我們發現3×Tg-AD小鼠相較於同齡的B6小鼠其空間學習能力較差，而且其膽鹼性神經元數量也大幅地減少。另外，我們也發現前處理PS128能避免B6或3×Tg-AD小鼠因急性側腦室注射STZ造成的認知功能缺陷並且伴隨著減少AD相關病理特徵，包括Aβ的堆積、神經發炎反應， BACE1蛋白質表現量上升與認知功能相關腦區神經元數量減損等，因此此研究揭露PS128益生菌對於阿茲海默氏症的治療潛力。Alzheimer's disease ( AD ) is the major type of dementia and AD patients are increased dramatically with the fast growing of aging population. The pathological hallmarks of AD are amyloid-β ( Aβ ) plaques and neurofibrillary tangles ( NFTs ) formed by aggregated hyperphosphorylated tau protein. However, the treatments using strategies of anti-Aβ or anti-tau phosphorylation still face challenges in clinical trials. Thus, there is an urgent need to explore novel therapeutic strategy in AD. Based on the hypothesis of gut-brain bidirectional axis, the consumption of probiotics prevents or delays the cognitive impairment induced by stress or intracerebroventricular Aβ injection. However, typical AD animal models were not tested in above probiotic studies. PS128 psychobiotic identified in Taiwan has showed beneficial effects on anti-anxiety, -depression, and -inflammation in stressed mice. Therefore, we evaluated the effects and molecular mechanisms of PS128 psycho-biotic supplementation in two AD animal models, the early-onset family AD ( FAD ) and sporadic AD ( SAD ). In the study, an acute intracerebroventricular streptozotocin ( icv-STZ; 3 mg/kg, 4 μl ) or saline was administrated in tripe transgenic AD ( 3×Tg-AD mice, as a model of FAD ) and C57BL/6J ( B6; as a model of SAD) male mice at 6 months old. Before STZ injection, all mice received PS128 or vehicle 100 μl ( 10^10 CFU/ml, orally gavage, once per day ) for total 33 days. At first, we found that a worse spatial learning curve and less cholinergic neurons were shown in 3×Tg-AD mice compared to B6 mice. In addition, pretreatment PS128 psychobiotic prevetnted icv-STZ induced cognitive dysfunction associated with decreasing of AD pathological features, including Aβ deposition, gliosis, BACE1 protein expression levels, and cognitive related neuronal loss. Therefore, the pretreatment PS128 psychobiotic could be a potential therapeutic strategy in AD.