探討疼痛和阿茲海默症的關聯性：臨床群體資料與果蠅模型分析

Abstract

阿茲海默症(AD)患者的疼痛感知在疾病進程中會改變，然而基於患者的認知功能、表達能力等缺陷使疼痛難以準確量化，目前已知研究對AD 造成的疼痛感受性差異說法不一，背後的機制也不明確。為了釐清AD對疼痛感受性的影響，我們使用兩種不同的資料庫─阿茲海默症神經影像學倡議 (ADNI) 群體資料和台灣人體資料庫，找出重要的瞬時受體電位受器，其中，只有TRPA1在APP/PS1小鼠腦部有顯著的RNA變化。在血液轉錄組檢測中，將TRPA1與疼痛、認知功能、腦體積以及失智症合併精神行為症進行分析，發現TRPA1在中輕度認知障礙 (MCI)族群中不僅與痛的表現有關聯性，同時也與AD有關聯性。然而，僅靠臨床群體分析無法有效地找出TRPA1在疼痛與AD之間具有關聯性的關鍵證據，因此，我們使用果蠅模型進一步釐清真相。 我們使用加熱板產生有害溫度，使果蠅感到疼痛，並觀察他們以跳躍迴避有害熱的反應時間，發現AD果蠅對疼痛反應較遲鈍，且這種現象可能受果蠅大腦中的TRPA1調控。為了進一步探索TRPA1在這一過程中的具體參與，我們在AD果蠅腦部過表現TRPA1，我們發現TRPA1不僅能介導AD相關的疼痛敏感性，還能改善AD疾病進展。綜上所述，果蠅模型分析的結果驗證了臨床群體分析中TRPA1對疼痛和AD的因果關聯性，這意味著TRPA1在AD相關疼痛感受性和AD疾病進展中扮演著一個關鍵角色。

Pain perception in patients with Alzheimer’s disease (AD) changes throughout the progression of the disease. However, due to impairments in cognitive function and expressive ability,pain is difficult to accurately quantify. Current studies offer inconsistent conclusions regarding alterations in pain sensitivity caused by AD, and the underlying mechanisms remain unclear. To clarify the impact of AD on pain sensitivity, we used two distinct databases—the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and the Taiwan Biobank—to identify key transient receptor potential (TRP) channels. Among them, only TRPA1 exhibit significant RNA changes in the brains of APP/PS1 mice. In transcriptomic analyses of blood samples, we further examined the associations of TRPA1 with pain, cognitive function, brain volume, and neuropsychiatric symptoms related to dementia. We found that TRPA1 is not only associated with pain manifestation in individuals with mildcognitive impairment (MCI), but also with the development of AD. However, clinical cohort analysis alone cannot effectively provide key evidence of a causal relationship between TRPA1, pain, and AD. Therefore, we used a Drosophila model to further investigate this connection. We applied noxious heat via a hot plate to induce pain in the flies and observed their latency to jump as an avoidance response. We found that AD model flies exhibited delayed pain responses, and this phenomenon may be regulated by TRPA1 in the fly brain. To further explore TRPA1’s specific involvement in this process, we overexpressed TRPA1 in the brains of AD flies. We discovered that TRPA1 not only mediates AD-related pain susceptibility but also ameliorates AD progression. In summary, findings from the Drosophila model validate the causal relationship between TRPA1, pain, and AD observed in clinical cohort analyses. This suggests that TRPA1 plays a key role in both AD related pain susceptibility and the progression of AD.