Thangeswaran Danesh, Shamsuddin Shaharum, Balakrishnan Venugopal
Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Minden, Penang, 11800, Malaysia.
School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia.
Mol Biol Rep. 2025 Aug 19;52(1):835. doi: 10.1007/s11033-025-10930-4.
Familial Alzheimer's disease (fAD) is a hereditary disease that develops at an unusually early age. The deposition of toxic amyloid-beta (Aβ) is a hallmark of fAD. Despite their genetic origin and increasing prevalence, no effective drugs currently exist. THICAPA, a novel compound containing a tetrahydroisoquinoline group of amines, is naturally found in the brain and food and has diverse medicinal properties. However, its potential role in modulating amyloidogenesis in patients with fAD has not yet been explored.
We investigated the effects of THICAPA on the amyloid precursor protein (APP) processing pathway in fibroblasts derived from patients with fAD. The in vitro cytotoxicity assay revealed no significant THICAPA cytotoxicity in fAD (AG06840) or healthy fibroblast cell lines (GM05879). Aβ scavenging assay revealed that 50 µM THICAPA potentially scavenged aged Aβ42 oligomers in the healthy fibroblast line. Gene and protein expression analyses revealed reduced APP expression and mature/immature APP expression ratio, BACE1 and presenilin 1 downregulation, and ADAM10 upregulation. Protein quantification revealed a significant reduction in C-terminal fragment beta, soluble APP (sAPP)β, and Aβ42/40 ratio in the amyloidogenic pathway and elevated sAPPα in the non-amyloidogenic pathway. Moreover, reactive oxygen species detection indicated that THICAPA reduced ROS production in fibroblasts from patients with fAD by 41.63%, although its intrinsic antioxidant properties were modest.
THICAPA attenuates amyloidogenesis and upregulates the non-amyloidogenic pathway while alleviating ROS production. These findings suggest that THICAPA is a potential therapeutic candidate for treating fAD.
家族性阿尔茨海默病（fAD）是一种在异常早的年龄发病的遗传性疾病。有毒淀粉样β蛋白（Aβ）的沉积是fAD的一个标志。尽管其具有遗传起源且患病率不断上升，但目前尚无有效的药物。THICAPA是一种含有四氢异喹啉胺基团的新型化合物，天然存在于大脑和食物中，具有多种药用特性。然而，其在调节fAD患者淀粉样蛋白生成中的潜在作用尚未得到探索。
我们研究了THICAPA对来自fAD患者的成纤维细胞中淀粉样前体蛋白（APP）加工途径的影响。体外细胞毒性试验显示，THICAPA在fAD（AG06840）或健康成纤维细胞系（GM05879）中无明显细胞毒性。Aβ清除试验显示，50μM THICAPA可能清除健康成纤维细胞系中老化的Aβ42寡聚体。基因和蛋白质表达分析显示APP表达降低，成熟/未成熟APP表达比值降低，β-分泌酶1（BACE1）和早老素1下调，而α-分泌酶（ADAM10）上调。蛋白质定量显示淀粉样蛋白生成途径中C末端片段β、可溶性APP（sAPP）β和Aβ42/40比值显著降低，而非淀粉样蛋白生成途径中sAPPα升高。此外，活性氧检测表明，尽管THICAPA的内在抗氧化特性一般，但其使fAD患者成纤维细胞中的活性氧产生减少了41.63%。
THICAPA可减轻淀粉样蛋白生成，上调非淀粉样蛋白生成途径，同时减轻活性氧的产生。这些发现表明THICAPA是治疗fAD的潜在候选药物。
