使用模式鼠探討益生菌PS23對阿茲海默症的預防治療潛力

Abstract

阿茲海默氏症(Alzheimer’s disease, AD) 的主要病理特徵為神經元內外β類澱粉蛋白 (β-amyloid, Aβ) 的堆積以及神經元內 Tau 蛋白過度磷酸化所造成神經纖維糾結 (neurofibrillary tangles, NFT)。但是截至目前為止並沒有有效治療阿茲海默氏症的方法。許多研究發現腸道以及大腦之間有所謂的「腸腦軸」的雙向連結，而腸胃道、中樞神經系統、周邊神經系統以及自主神經系統都參與其中。目前認為益生菌可以改善腸道微生物菌相並透過腸腦軸去影響大腦。PS23是從健康人體的糞便中所取得的副乾酪乳桿菌 (Lactobacillus paracasei)，目前已經有許多關於PS23改善神經退化性疾病之研究，這些研究發現PS23可以延緩小鼠的老化進程以及老化所引起的記憶力衰退，還可以降低小鼠的慢性焦慮以及憂鬱行為，但目前並沒有PS23對於阿茲海默氏症的研究發表。在本實驗中，我們發現在行為實驗中，管餵給予阿茲海默氏症小鼠PS23無法顯著恢復短期記憶以及空間學習的能力，但有挽救Aβ所造成損傷程度之趨勢。而在AD小鼠中，管餵活菌PS23可以顯著提升AD小鼠與神經元活性相關的突觸素 (synaptophysin) 以及顯著降低發炎相關指標caspase-1活性，管餵死菌 PS23則可以顯著降低蛋白質因為氧化壓力而產生的碳基含量。因此，我們推測PS23可能是透過腸腦軸去改變神經元活性、抑制發炎以及減緩氧化壓力來去改善AD之病徵。

Alzheimer’s disease (AD) is currently the most common type of dementia, and the main symptoms are memory loss and confusion with time or place. The pathological characteristics of AD are insoluble β-amyloid (Aβ) plaques formed from Aβ accumulation and neurofibrillary tangles (NFTs) caused by tau protein hyper-phosphorylation. However, currently, there are no effective therapies for AD. Research has discovered that there is communication along the gut-brain axis, in which the gastrointestinal tract (GI tract), central nervous system (CNS), autonomic nervous system (ANS), and immune system are involved. Probiotics are believed to help improving enteric microflora and affect the brain through the gut-brain axis. PS23 is Lactobacillus paracasei isolated from healthy human feces, and studies show that PS23 can ameliorate different neurodegenerative symptoms in mouse models, including cognitive decline, aging progression, and depression. However, there is no report on the effect of PS23 on AD. In this study, we show that PS23 showed a tendency of improving in short-term memory and spatial learning ability in behavior tests, however, this trend did not reach statistical significance. AD mice that were administered with Live-PS23 (L-PS23), showed synaptophysin was increased in the hippocampus. Synaptophysin is a synaptic vesicle protein associated with neuron activity. In addition, the inflammation biomarker caspase-1 was decreased in the hippocampus after the L-PS23 administration, and H-PS23 induced protein carbonylation levels cause by reactive oxygen species. These results suggest that PS23 may affect AD through the gut-brain axis to reduce inflammation and oxidative stress and improve the synapse survival.