Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer’s disease condition in rats

Violina Kakoty, Sarathlal K C, Sunil Kumar Dubey, Chih Hao Yang, Sandhya Amol Marathe, Rajeev Taliyan

Research output: Contribution to journalArticlepeer-review

Abstract

Insulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer’s Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aβ1–42 treated SH-SY5Y cells were exposed to rapa (20 μM) and vori (4 μM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aβ1–42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1–42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.

Original languageEnglish
Pages (from-to)927-944
Number of pages18
JournalMetabolic Brain Disease
Volume37
Issue number4
DOIs
Publication statusPublished - Apr 2022

Keywords

  • Alzheimer’s disease
  • Autophagy
  • Histone deacetylase inhibitor
  • Insulin resistance
  • Rapamycin
  • Vorinostat

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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