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Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer’s Disease (sAD)-Like Pathology

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer’s disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

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Abbreviations

sAD:

Sporadic Alzheimer’s disease

CNS:

Central nervous system

NMDA:

N-methyl-D-aspartate receptor

Aβ:

Beta amyloid

APP:

Amyloid precursor protein

NFT:

Neurofibrillary tangle

STZ:

Streptozotocin

IRS:

Insulin receptor signaling

IR:

Insulin receptor

GLT:

Glucose transporter

IRBS:

Insulin-resistant brain state

OGlcNAc:

O-glucose-N-acetyl

ICV:

Intracerebroventricular

GSK-3β:

Glycogen synthase-3β

PKC:

Protein kinase C

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Acknowledgments

This work was supported in part by the Council of Scientific and Industrial Research (CSIR), India, and financial support to Pradip Kumar Kamat from National Institute of Health, USA, is greatly acknowledged. We are thankful to Dr. Maneesh K. Gupta for the supports for drawing chemical structures (The Hebrew University, Jerusalem), Israel.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease (CTRND), College of Medicin, University of Florida, Gainesville, FL, 32610, USA

    Pradip K. Kamat & Abdullah S. Ahmad

  2. Division of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

    Anuradha Kalani

  3. Division of Pharmacology, CSIR-Central drug Research Institute (CDRI), Lucknow, 226031, India

    Shivika Rai & Santosh Kumar Tota

  4. The Academy of Scientific & Innovative Research (AcSIR), New Delhi, 110025, India

    Shivika Rai

  5. McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    Ashok Kumar

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  1. Pradip K. Kamat
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  2. Anuradha Kalani
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  3. Shivika Rai
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  4. Santosh Kumar Tota
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Correspondence to Pradip K. Kamat.

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Kamat, P.K., Kalani, A., Rai, S. et al. Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer’s Disease (sAD)-Like Pathology. Mol Neurobiol 53, 4548–4562 (2016). https://doi.org/10.1007/s12035-015-9384-y

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  • DOI: https://doi.org/10.1007/s12035-015-9384-y

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