Skip to main content

Advertisement

SpringerLink
Log in

Nmnat1 Modulates Mitochondrial Oxidative Stress by Inhibiting Caspase-3 Signaling in Alzheimer’s Disease

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Nigrostriatal pathway disturbance is one of the major pathogenic factors in Alzheimer’s disease (AD). Dopaminergic neuron dysfunction results in bradykinesia and akinesia (inability to initiate movement), indicating a significant risk factor for substantia nigra pars compacta lesions. Furthermore, the nicotinamide adenine dinucleotide (NAD+) is associated with Aβ toxicity decline in AD therapy. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is an essential enzyme that preserves normal neuronal function and protects neurons from insult. This study aimed to investigate the potential therapeutic effects of Nmnat1 and its underlying mechanisms in a triple-transgenic mouse model of AD (3xTgAD). Results showed that Nmnat1 improved the substantial behavioral measures of cognitive impairments compared with the 3xTgAD control. Additionally, Nmnat1 overexpression significantly increased tyrosine hydroxylase-positive neurons and anti-apoptotic protein Bcl2 and caspase-3 expression levels in 3xTgAD mice. Nmnat1 also effectively controlled SOD1 activation. In conclusion, Nmnat1 substantially decreases multiple AD-associated pathological characteristics at least partially by the increase of caspase-3 activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Berger F, Ramírez-Hernández MH, Ziegler M (2004) The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci 29:111–118

    Article  CAS  Google Scholar 

  • Browne SE, Beal MF (1994) Oxidative damage and mitochondrial dysfunction in neurodegenerative diseases. Biochem Soc Trans 22:1002–1006

    Article  CAS  Google Scholar 

  • Burns JM, Galvin JE, Roe CM, Morris JC, McKeel DW (2005) The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 64:1397–1403

    Article  CAS  Google Scholar 

  • Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT (2010) Loss of tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience 169:516–531

    Article  CAS  Google Scholar 

  • Dlugosz PJ, Billen LP, Annis MG, Zhu W, Zhang Z, Lin J, Leber B, Andrews DW (2006) Bcl-2 changes conformation to inhibit Bax oligomerization. Embo j 25:2287–2296

    Article  CAS  Google Scholar 

  • Donmez G (2012) The effects of SIRT1 on Alzheimer’s disease models. Int J Alzheimers Dis 2012:509529

    PubMed  PubMed Central  Google Scholar 

  • Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL (2003) Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 100:10417–10422

    Article  CAS  Google Scholar 

  • Jellinger KA (2003) Alpha-synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106:191–201

    Article  Google Scholar 

  • Kapogiannis D, Mattson MP (2011) Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol 10:187–198

    Article  CAS  Google Scholar 

  • Lane CA, Hardy J, Schott JM (2018) Alzheimer’s disease. Eur J Neurol 25:59–70

    Article  CAS  Google Scholar 

  • Leem E, Oh YS, Shin WH, Jin BK, Jeong JY, Shin M, Kim DW, Jang JH, Kim HJ, Ha CM, Jung UJ, Moon GJ, Kim SR (2019) Effects of silibinin against prothrombin kringle-2-induced neurotoxicity in the nigrostriatal dopaminergic system in vivo. J Med Food 22:277–285

    Article  CAS  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  CAS  Google Scholar 

  • McMillan PJ, White SS, Franklin A, Greenup JL, Leverenz JB, Raskind MA, Szot P (2011) Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson’s disease and Alzheimer’s disease. Brain Res 1373:240–252

    Article  CAS  Google Scholar 

  • Musiek ES, Xiong DD, Patel T, Sasaki Y, Wang Y, Bauer AQ, Singh R, Finn SL, Culver JP, Milbrandt J, Holtzman DM (2016) Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy. Ann Clin Transl Neurol 3:434–442

    Article  CAS  Google Scholar 

  • Nopparat C, Porter JE, Ebadi M, Govitrapong P (2014) 1-Methyl-4-phenylpyridinium-induced cell death via autophagy through a Bcl-2/Beclin 1 complex-dependent pathway. Neurochem Res 39:225–232

    Article  CAS  Google Scholar 

  • Perez SE, Lazarov O, Koprich JB, Chen EY, Rodriguez-Menendez V, Lipton JW, Sisodia SS, Mufson EJ (2005) Nigrostriatal dysfunction in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 transgenic mice. J Neurosci 25:10220–10229

    Article  CAS  Google Scholar 

  • Renaud J, Bassareo V, Beaulieu J, Pinna A, Schlich M, Lavoie C, Murtas D, Simola N, Martinoli MG (2018) Dopaminergic neurodegeneration in a rat model of long-term hyperglycemia: preferential degeneration of the nigrostriatal motor pathway. Neurobiol Aging 69:117–128

    Article  CAS  Google Scholar 

  • Rosario ER, Carroll JC, Oddo S, LaFerla FM, Pike CJ (2006) Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci 26:13384–13389

  • Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD(+) depletion. Elife 5:e19749

    Article  Google Scholar 

  • Sun C, Ou X, Farley JM, Stockmeier C, Bigler S, Brinton RD, Wang JM (2012) Allopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 9:473–480

    Article  CAS  Google Scholar 

  • Wen Y, Parrish JZ, He R, Zhai RG, Kim MD (2011) Nmnat exerts neuroprotective effects in dendrites and axons. Mol Cell Neurosci 48:1–8

    Article  CAS  Google Scholar 

  • Whitmore AV, Lindsten T, Raff MC, Thompson CB (2003) The proapoptotic proteins Bax and Bak are not involved in Wallerian degeneration. Cell Death Differ 10:260–261

    Article  CAS  Google Scholar 

  • Yan T, Feng Y, Zhai Q (2010) Axon degeneration: Mechanisms and implications of a distinct program from cell death. Neurochem Int 56:529–534

    Article  CAS  Google Scholar 

  • Ying W (2008) NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 10:179–206

    Article  CAS  Google Scholar 

  • Zhai RG, Zhang F, Hiesinger PR, Cao Y, Haueter CM, Bellen HJ (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452:887–891

    Article  CAS  Google Scholar 

  • Zhao H, Zhang JY, Yang ZC, Liu M, Gang BZ, Zhao QJ (2011) Nicotinamide mononucleotide adenylyltransferase 1 gene NMNAT1 regulates neuronal dendrite and axon morphogenesis in vitro. Chin Med J (Engl) 124:3373–3377

    CAS  Google Scholar 

Download references

Funding

This study was supported by Yangpu Hospital Sel201822 (to ZW.Y) and Yangpu Hospital Sel201807 (to HY.J).

Author information

Author notes

  1. Huayu Jiang and Zhiwen Wan equally contributed to this work and should be considered as equal first coauthors.

Authors and Affiliations

  1. Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, China

    Huayu Jiang, Zhiwen Wan, Ying Ding & Zhiwen Yao

Authors
  1. Huayu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiwen Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiwen Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhiwen Yao.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, H., Wan, Z., Ding, Y. et al. Nmnat1 Modulates Mitochondrial Oxidative Stress by Inhibiting Caspase-3 Signaling in Alzheimer’s Disease. J Mol Neurosci 71, 1467–1472 (2021). https://doi.org/10.1007/s12031-020-01781-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-020-01781-8

Keywords

Search

Navigation