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

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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.

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Data Availability

All data generated or analysed during this study are included in the manuscript.

Code Availability

Not applicable.

Abbreviations

AD:

:Alzheimer’s disease

APPβ:

:Amyloid precursor proteinbeta

ATF4:

:Activating transcription factor 4

Aβ:

:Amyloid beta

BACE1:

:Beta-site APP cleaving enzyme 1

BSA:

:Bovine serum albumin

CA1:

:Cornu ammonis-1

CA2:

:Cornu ammonis-2

CA3:

:Cornu ammonis-3

CV:

:Cresyl violet

DAPI:

:4′,6-diamidino-2-phenylindole

DG:

:Dentate gyrus

DMEM:

:Dulbecco’s modified essential medium

EMEM:

:Eagles modified essential medium

FBS:

:Foetal bovine serum

FESEM:

:Field emission scanning electron microscopy

FGF21:

:Fibroblast growth factor 21

GFAP:

:Glial fibrillary acidic protein

GFP:

:Green fluorescent protein

GSH:

:Reduced Glutathione

H&E:

:Haematoxylin & eosin

HFIP:

:Hexafluoroisopropanol

IBA-1:

:Ionized calcium binding adaptor molecule 1

ICV:

:Intra-cerebroventricular

IR:

:Insulin resistance

LAMP-2:

:Lysosomal associated membrane protein-2

LC3:

:Microtubule-associated protein 1A/1B-light chain 3

LV:

:Lentiviral vector

MDA:

:Malondialdehyde

mtDNA:

:Mitochondrial deoxyribonucleic

mTORC1:

:Mechanistic target of rapamycin complex 1

MWM:

:Morris water maze

NC:

:Normal control

NFTs:

:Neurofibrillary tangles

PBS:

:Phosphate buffer saline

PEG:

:Poly (ethylene glycol) methyl ether

PFA:

:Paraformaldehyde

ptau:

:phosphorylated tau

qRT-PCR:

:Real-time quantitative polymerase chain reaction

RAM:

:Radial arm maze

RAM:

:Radial arm maze

Rapa:

:Rapamycin

RNA:

:Ribonucleic acid

sAPPβ:

:Soluble amyloid precursor proteinbeta

SOD:

:Superoxide Dismutase

UPRmt:

:Mitochondrial unfolded protein response

VP:

:Vector plasmid

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Acknowledgements

Authors are thankful to Birla Institute of Technology and Science-Pilani (BITS-Pilani), Pilani Campus, Rajasthan, India; Taipei Medical University (TMU), Taipei, Taiwan; and Indian Council for Medical Research (ICMR), New Delhi, India, for their support for this study.

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Authors and Affiliations

  1. Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India, 333031

    Violina Kakoty, Sarathlal K C, Shobha Kumari & Rajeev Taliyan

  2. Department of Pharmacology, Taipei Medical University, Taipei, Taiwan, 110

    Chih-Hao Yang

  3. R&D Healthcare Division, Emami Ltd, Kolkata, India, 700107

    Sunil Kumar Dubey

Authors
  1. Violina Kakoty
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  2. Sarathlal K C
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  4. Shobha Kumari
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  5. Sunil Kumar Dubey
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  6. Rajeev Taliyan
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Contributions

Violina Kakoty, Rajeev Taliyan, Sunil Kumar Dubey, Chih HaoYang, designed the study protocol, Violina Kakoty and Sarathlal KC performed the experiments, analysed, interpreted the data and wrote the manuscript, Violina Kakoty and Shobha Kumari processed the rat brain sections for histochemical analysis and captured the images. Violina Kakoty and Chih Hao Yang analysed the western blot, histochemical and immunofluorescence results, Rajeev Taliyan proof read the entire manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Rajeev Taliyan.

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This study was performed in line with the principles of the Institutional Animal ethics committee, BITS-Pilani, Pilani campus, Rajasthan, India (IAEC/RES/30/07).

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The authors declare no competing interests.

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Kakoty, V., C, S.K., Yang, CH. et al. Neuroprotective Effect of Lentivirus-Mediated FGF21 Gene Delivery in Experimental Alzheimer’s Disease is Augmented when Concerted with Rapamycin. Mol Neurobiol 59, 2659–2677 (2022). https://doi.org/10.1007/s12035-022-02741-6

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  • DOI: https://doi.org/10.1007/s12035-022-02741-6

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