A Synthetic Pro-Drug Peptide Reverses Amyloid-β-Induced Toxicity in the Rat Model of Alzheimer’s Disease

Article type: Research Article

Authors: Kumar, Sourav^{a; 1} | Srivastav, Saurabh^{c; 1} | Fatima, Mahino^c | Giri, Rajat Subhra^b | Mandal, Bhubaneswar^b | Mondal, Amal Chandra^{a; c; *}

Affiliations: [a] Neuroscience Research Unit, Department of Physiology, RPM College, Uttarpara, Hooghly, West Bengal, India | [b] Laboratory of Peptide Research, Department of Chemistry, Indian Institute of Technology Guwahati (IITG), North Guwahati, Assam, India | [c] Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Correspondence: [*] Correspondence to: Dr. Amal Chandra Mondal, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India. Tel.: +91 11 2670 4505; E-mail: acmondal@mail.jnu.ac.in.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, involves the formation of the extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. The current therapies against AD are symptomatic with limited benefits but associated with major side effects. Inhibition of self-aggregation of Aβ peptides into higher order cross-β structure is one of the potential therapeutic approach which may counter oligomerization of Aβ peptide. Objective:The present study aimed to evaluate the neuroprotective and anti-inflammatory potential of a synthetic Pro-Drug type peptide (PDp) against Aβ-induced toxicity in rat model of AD. Methods:Intra-hippocampal microinjection of toxic Aβ40 (IHAβ40) by stereotaxic surgery was performed in the male Sprague-Dawley rats to generate an Aβ-induced AD model. Sub-chronic toxicity of synthetic PDp using hematological, biochemical, and histopathological parameters was investigated. Evaluation of PDp on Aβ-induced neurodegeneration and neuroinflammation was performed. Results:PDp inhibits plaque formation with increase in Nissl granule staining in the rat hippocampus. Aβ-induced toxicity associated imbalance in reactive oxygen species and antioxidant enzymes activity such as superoxide dismutase and catalase in the rat brain was overcome by PDp treatment. Tau protein hyperphosphorylation was normalized with PDp treatment. Also, the neuroinflammatory response was suppressed with PDp treatment. Conclusion:The present study depicts the potential neuroprotective role of PDp against Aβ-induced toxicity in rat. PDp inhibits plaque formation thereby normalizing oxidative stress, inhibiting tau protein hyperphosphorylation, and suppressing neuroinflammatory responses. Future studies done in this direction will pave way for new therapeutic strategies.

Keywords: Alzheimer’s disease, amyloid-β₄₀, neuroinflammation, neuroprotection, Pro-Drug type peptide, rat model of AD

DOI: 10.3233/JAD-181273

Journal: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 499-512, 2019