Time-dependent effect of oligomeric amyloid-β (1–42)-induced hippocampal neurodegeneration in rat model of Alzheimer’s disease

ABSTRACT

Objective: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aβ) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aβ influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aβ_(1–42) (oAβ_1–42) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD.

Methods: Aggregated forms of synthetic Aβ peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription–polymerase chain reaction.

Results: oAβ_1–42 decreased the gene expression level of α7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAβ_1–42 aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, amyloid-β_1–42 are highly expressed in 15 days after postinjection in hippocampus of adult rats.

Conclusion: Acute exposure of oAβ_1–42 modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments.

Abbreviations: AD: Alzheimer’s disease, Aβ: amyloid-β; oAβ_1–42: oligomeric amyloid-β 1–42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d-aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; α7-nAChR: α7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T.

KEYWORDS:

• Alzheimer’s disease
• amyloid-β
• hippocampus
• NMDA receptor
• acetylcholine receptor
• spatial learning and memory

Acknowledgments

The authors gratefully acknowledge Council of Scientific and Industrial Research (CSIR) for the Senior Research Fellowship to Chennakesavan Karthick (09/475 (0194)/2014-EMR-I). The infrastructure of our department is supported by the Department of Science and Technology-Fund for Improvement of S and T Infrastructure in Universities and Higher Educational Institutions (DST-FIST). We express gratitude toward Prof. Radhakrishnan, Department of Marine Science, Bharathidasan University, India, for his assistance with birefringent studies. The authors are additionally thankful to Dr. Antony Joseph Velanganni, Bharathidasan University, for his help with fluorescent microscopic analysis.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplementary data for this article can be accessed here.

Additional information

Notes on contributors

Chennakesavan Karthick

Chennakesavan Karthick is currently a postdoctoral fellow of Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University. He completed his Doctoral research in the field of Neurodegeneration. He has developed two model systems on rat model for AD. His research mainly focuses on identifying key issues that facilitate Alzheimer’s treatment at the early stages. In his record, he holds many international publications in the field of neuroscience and notably, his publication in Frontiers in Neuroscience is of significance.

Saravanan Nithiyanandan

Saravanan Nithyanandan is currently a doctorate scholar in Department of Biochemistry. During his Master’s at Department of Biochemistry, he executed his project in the field of neuroscience in particular on Alzheimer’s Disease. He has contributed to the current manuscript to a great extent in getting the AD model and performed behavioral analysis.

Musthafa Mohamed Essa

M. Mohamed Essa is an Associate Professor of Nutrition at Sultan Qaboos University, Oman and holding visiting A/Prof position in Neuropharmacology group, ASAM, Macquarie University, Sydney, Australia. He is an expert in the field of Nutritional Neuroscience and published 84 papers, 31 book chapters and 7 books (4 published and 3 in press). He is holding memberships in various international bodies including American Society for Neurochemistry (ASN), International Society for Neurochemistry (ISN), etc. He has received so many awards from local and international bodies and this year one of his book titled “Food and Brain health” was awarded as best book in the World by GOURMAND Cook Book Awards.

Gilles J Guillemin

Gilles Guillemin is one of the world’s leading scientist studying neuroactive (toxic or protective or immunomodulator) metabolites derived from tryptophan metabolism and their involvement in several neurodegenerative diseases. Over the last two decades, he demonstrated the importance of this pathway in multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis, which has opened numerous new promising research avenues and has translated to important new prognostic and therapeutic strategies. Through his international and national collaborative network, Prof Guillemin and his research team have extended their research to other diseases such as Parkinson’s disease, suicide, depression, autism, schizophrenia breast cancers and brain tumours.

Swaminathan K Jayachandran

Swaminathan K Jayachandran is a leading scientist in India working in the field of cardiovasacular diseases and stroke. He has developed invivo model for Ischemic / Reperfusion (I/R) in Guinea pigs and got many international publications from highly reputed Journals. He is currently focusing his research in understanding the role of PS2 (Presenilin – 2) in brain of rats in response to I/R injury.