Neuroprotective Effect of Lentivirus-Mediated FGF21 Gene Delivery in Experimental Alzheimer’s Disease is Augmented when Concerted with Rapamycin

Violina Kakoty, K. C. Sarathlal, Chih Hao Yang, Shobha Kumari, Sunil Kumar Dubey, Rajeev Taliyan

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer type of dementia is accompanied with progressive loss of cognitive function that directly correlates with accumulation of amyloid beta plaques. It is known that Fibroblast growth factor 21 (FGF21), a metabolic hormone, with strong neuroprotective potential, is induced during oxidative stress in Alzheimer’s disease. Interestingly, FGF21 cross-talks with autophagy, a mechanism involved in the clearance of abnormal protein aggregate. Moreover, autophagy activation by Rapamycin delivers neuroprotective role in Alzheimer’s disease. However, the synergistic neuroprotective efficacy of overexpressed FGF21 along with Rapamycin is not yet investigated. Therefore, the present study examined whether overexpressed FGF21 along with autophagy activation ameliorated neurodegenerative pathology in Alzheimer’s disease. We found that cognitive deficits in rats with intracerebroventricular injection of Amyloid beta1-42 oligomers were restored when injected with FGF21-expressing lentiviral vector combined with Rapamycin. Furthermore, overexpression of FGF21 along with Rapamycin downregulated protein levels of Amyloid beta1-42 and phosphorylated tau and expression of major autophagy proteins along with stabilization of oxidative stress. Moreover, FGF21 overexpressed rats treated with Rapamycin revamped the neuronal density as confirmed by histochemical, cresyl violet and immunofluorescence analysis. These results generate compelling evidence that Alzheimer’s disease pathology exacerbated by oligomeric amyloid beta may be restored by FGF21 supplementation combined with Rapamycin and thus present an appropriate treatment paradigm for people affected with Alzheimer’s disease. Graphical abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)2659-2677
Number of pages19
JournalMolecular Neurobiology
Volume59
Issue number5
DOIs
Publication statusPublished - May 2022

Keywords

  • Alzheimer’s disease
  • Autophagy
  • Fibroblast growth factor 21
  • Lentiviral vector
  • Rapamycin

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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