Journal of Molecular Neuroscience

, Volume 69, Issue 2, pp 264–285 | Cite as

Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS

  • Ella Zeldich
  • Ci-Di Chen
  • Emma Boden
  • Bryce Howat
  • Jason S. Nasse
  • Dean Zeldich
  • Anthony G. Lambert
  • Andrea Yuste
  • Jonathan D. Cherry
  • Rebecca M. Mathias
  • Qicheng Ma
  • Nelson C. Lau
  • Ann C. McKee
  • Theo Hatzipetros
  • Carmela R. AbrahamEmail author


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. ALS neuropathology is associated with increased oxidative stress, excitotoxicity, and inflammation. We and others reported that the anti-aging and cognition-enhancing protein Klotho is a neuroprotective, antioxidative, anti-inflammatory, and promyelinating protein. In mice, its absence leads to an extremely shortened life span and to multiple phenotypes resembling human aging, including motor and hippocampal neurodegeneration and cognitive impairment. In contrast, its overexpression extends life span, enhances cognition, and confers resistance against oxidative stress; it also reduces premature mortality and cognitive and behavioral abnormalities in an animal model for Alzheimer’s disease (AD). These pleiotropic beneficial properties of Klotho suggest that Klotho could be a potent therapeutic target for preventing neurodegeneration in ALS. Klotho overexpression in the SOD1 mouse model of ALS resulted in delayed onset and progression of the disease and extended survival that was more prominent in females than in males. Klotho reduced the expression of neuroinflammatory markers and prevented neuronal loss with the more profound effect in the spinal cord than in the motor cortex. The effect of Klotho was accompanied by reduced expression of proinflammatory cytokines and enhanced the expression of antioxidative and promyelinating factors in the motor cortex and spinal cord of Klotho × SOD1 compared to SOD1 mice. Our study provides evidence that increased levels of Klotho alleviate ALS-associated pathology in the SOD1 mouse model and may serve as a basis for developing Klotho-based therapeutic strategies for ALS.


Amyotrophic lateral sclerosis Neurodegeneration Microglia Neuroinflammation Motor neurons Therapeutics 



A disintegrin and metalloprotease domain


Amyotrophic lateral sclerosis


ALS Therapy Development Institute


Alzheimer’s disease

Axin 2

Axin-related protein 2


Anterior horn cells


Chromosome 9 open reading frame 72


Cerebrospinal fluid


C-C chemokine receptor type 2




Familial amyotrophic lateral sclerosis


Fibroblast growth factor receptors


Forkhead box O


Frizzled gene family encoding 7-transmembrane domain proteins


Glial fibrillary acidic protein


Hank’s balanced salt solution


Ionized calcium-binding adaptor molecule 1




Insulin-like growth factor 1














Inducible nitric oxide synthase


Myelin-associated glycoprotein


Myelin basic protein


Motor neurons


Multiple sclerosis






Proteolipid protein 1


Recombinant mouse Klotho


Neuronal nuclei


Nuclear factor-κB


Nitric oxide synthase


Nuclear factor erythroid 2-related factor 2


Neurological score


The activated type I receptors interact with and phosphorylate SMAD (an acronym for the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad) proteins to transduce signals


Superoxide dismutase


TAR DNA-binding protein 43


Transforming growth factor-β


Tumor necrosis factor-α


TNF alpha-induced protein 2


Quantitative reverse transcription polymerase chain reaction


Vascular endothelial growth factor


Wnt is an acronym that stands for “Wingless/Integrated”


Wild type



The authors wish to thank Dr. Douglas Rosene for his help with statistical analysis.

Authors’ Contributions

EZ, CDC, and CRA conceived the project. EZ, TH, and CRA designed the study. EZ, CDC, EB, BH, JSN, DZ, AGL, and AY performed the experiments in the laboratory of CRA and JDC and RMM in the laboratory of ACM. NCL and QM participated in the RNAseq analyses. All authors contributed to the analyses and/or interpreted the data. EZ wrote the paper with contributions from JSN, TH, and CRA. All authors read and approved the final manuscript.

Funding Information

This work was supported by NIH grants R01-AG052465 to NCL and R56-AG051638 to CRA.

Compliance with Ethical Standards

All animal procedures were performed in accordance with a protocol approved by the Boston University Institutional Animal Care and Use Committee.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ella Zeldich
    • 1
    • 2
  • Ci-Di Chen
    • 1
    • 2
  • Emma Boden
    • 1
  • Bryce Howat
    • 3
  • Jason S. Nasse
    • 1
  • Dean Zeldich
    • 3
  • Anthony G. Lambert
    • 3
  • Andrea Yuste
    • 2
  • Jonathan D. Cherry
    • 4
  • Rebecca M. Mathias
    • 4
    • 5
  • Qicheng Ma
    • 1
  • Nelson C. Lau
    • 1
    • 6
  • Ann C. McKee
    • 4
    • 5
    • 7
  • Theo Hatzipetros
    • 8
  • Carmela R. Abraham
    • 1
    • 2
    • 9
    Email author
  1. 1.Department of BiochemistryBoston University School of MedicineBostonUSA
  2. 2.Klogene Therapeutics, Inc.BostonUSA
  3. 3.Department of Biomedical EngineeringBoston UniversityBostonUSA
  4. 4.Department of NeurologyBoston University School of MedicineBostonUSA
  5. 5.Veterans Administration Boston Healthcare SystemBostonUSA
  6. 6.Genome Science InstituteBoston University School of MedicineBostonUSA
  7. 7.Department of PathologyBoston University School of MedicineBostonUSA
  8. 8.ALS Therapy Development InstituteCambridgeUSA
  9. 9.Department of Pharmacology and Experimental TherapeuticsBoston University School of MedicineBostonUSA

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