Manuj Ahuja1, Manal Buabeid1, Engy Abdel-Rahman2, Mohammed Majrashi1, Kodeeswaran Parameshwaran1, Rajesh Amin1, Sindhu Ramesh1, Kariharan Thiruchelvan1, Satyanarayana Pondugula3, Vishnu Suppiramaniam1, Muralikrishnan Dhanasekaran4. 1. Department of Drug Discovery and Development, Harrison School of Pharmacy (HSOP), Auburn University, AL 36849, USA. 2. Department of Drug Discovery and Development, Harrison School of Pharmacy (HSOP), Auburn University, AL 36849, USA; Center for Aging and Associated Diseases, Helmy Institute of Medical Sciences, Zewail City of Science and Technology, Giza, Egypt. 3. Department of Anatomy and Physiology, College of Veterinary Science, Auburn University, AL 36849, USA. 4. Department of Drug Discovery and Development, Harrison School of Pharmacy (HSOP), Auburn University, AL 36849, USA. Electronic address: dhanamu@auburn.edu.
Abstract
AIMS: Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimer's disease, although supportive experimental evidence remains undiscovered. Therefore, the current study was carried out to better understand and establish the pathophysiological involvement of chronic inflammation in a double transgenic mouse model of Alzheimer's disease. MAIN METHODS: We analyzed amyloid-beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10month old (APΔE9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings. KEY FINDINGS: Substantial increases in amyloid-beta levels, beta-secretase activity, and oxidative stress, along with significant neurochemical alterations in glutamate and GABA levels were detected in the brain of APΔE9 mice. Interestingly, marked elevations of pro-inflammatory cytokines in whole brain lysate of APΔE9 mice were observed. Flow cytometric analysis revealed a higher frequency of CD4+ IL-17a and IFN-γ secreting T-cells in APΔE9 brain, indicating a robust T-cell infiltration and activation. Behavioral deficits in learning and memory tasks, along with impairment in long-term potentiation and associated biochemical changes in the expression of glutamatergic receptor subunits were evident. SIGNIFICANCE: Thus, this study establishes the role by which oxidative stress, alterations in glutamate and GABA levels and inflammation increases hippocampal and cortical neurotoxicity resulting in the cognitive deficits associated with Alzheimer's disease.
AIMS: Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimer's disease, although supportive experimental evidence remains undiscovered. Therefore, the current study was carried out to better understand and establish the pathophysiological involvement of chronic inflammation in a double transgenic mouse model of Alzheimer's disease. MAIN METHODS: We analyzed amyloid-beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10month old (APΔE9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings. KEY FINDINGS: Substantial increases in amyloid-beta levels, beta-secretase activity, and oxidative stress, along with significant neurochemical alterations in glutamate and GABA levels were detected in the brain of APΔE9 mice. Interestingly, marked elevations of pro-inflammatory cytokines in whole brain lysate of APΔE9 mice were observed. Flow cytometric analysis revealed a higher frequency of CD4+ IL-17a and IFN-γ secreting T-cells in APΔE9 brain, indicating a robust T-cell infiltration and activation. Behavioral deficits in learning and memory tasks, along with impairment in long-term potentiation and associated biochemical changes in the expression of glutamatergic receptor subunits were evident. SIGNIFICANCE: Thus, this study establishes the role by which oxidative stress, alterations in glutamate and GABA levels and inflammation increases hippocampal and cortical neurotoxicity resulting in the cognitive deficits associated with Alzheimer's disease.
Authors: Mohammed Majrashi; Ayaka Fujihashi; Mohammed Almaghrabi; Maali Fadan; Eddie Fahoury; Sindhu Ramesh; Manoj Govindarajulu; Haley Beamon; Chastity N Bradford; Olga Bolden-Tiller; Muralikrishnan Dhanasekaran Journal: Vet Med Sci Date: 2020-07-06