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  1. Thangeswaran D, Shamsuddin S, Balakrishnan V
    Mol Biol Rep, 2025 Aug 19;52(1):835.
    PMID: 40828210 DOI: 10.1007/s11033-025-10930-4
    BACKGROUND: 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.

    METHODS AND RESULTS: 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.

    CONCLUSIONS: 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.

    Matched MeSH terms: Presenilin-1/metabolism
  2. Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Makpol S, et al.
    J Alzheimers Dis, 2019;72(1):229-246.
    PMID: 31594216 DOI: 10.3233/JAD-181171
    Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer's disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation.
    Matched MeSH terms: Presenilin-1/metabolism
  3. Durani LW, Hamezah HS, Ibrahim NF, Yanagisawa D, Nasaruddin ML, Mori M, et al.
    J Alzheimers Dis, 2018;64(1):249-267.
    PMID: 29889072 DOI: 10.3233/JAD-170880
    We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.
    Matched MeSH terms: Presenilin-1/metabolism
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