Multifaceted neuroprotective approach of Trolox in Alzheimer's disease mouse model: targeting Aß pathology, neuroinflammation, oxidative stress, and synaptic dysfunction

Muhammad Tahir, Min Hwa Kang, Tae Ju Park, Jawad Ali, Kyonghwan Choe, Jun Sung Park, Myeong Ok Kim*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (A beta) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an A beta(1 - 42)-induced AD mouse model. A beta(1 - 42) 5 mu L/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of A beta, phosphorylated tau (p-tau), and beta-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kappa B (pNF-kappa B) and interleukin-1 beta (IL-1 beta), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.
Original languageEnglish
Article number1453038
Number of pages15
JournalFrontiers in Cellular Neuroscience
Volume18
DOIs
Publication statusPublished - 17 Sept 2024

Keywords

  • Alzheimer's disease (AD)
  • amyloid beta plaques (A beta)
  • neurofibrillary tangles (NFTs)
  • Trolox
  • neuroinflammation
  • oxidative stress and neurodegeneration
  • VITAMIN-E
  • TOCOPHEROL
  • APOPTOSIS
  • TOXICITY
  • PEPTIDE
  • DAMAGE
  • BACE1

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