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Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APP swe and PS1 dE9 mutations

ABSTRACT: Neural stem cells (NSCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer’s Disease (AD). Modulating the development of these cells with inflammation-related peptides, like bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules on the genetic load of treated neurospheres. To facilitate an understanding of the wider biological processes in the context of neuroinflammation, we performed a global gene expression analysis on the transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD. We then performed a comparative analysis of the transcriptional profiles between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparing our data with human datasetd from AD patients. We observed that the treatments modulated the expression of genes mainly related to neuroinflammation mediated by microglia, with BK promoting an increase in the expression of genes that enrich processes, pathways, and cellular components related to immune impairment, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 acting on reduction of AD-related anomalies caused in this system. Our results reinforce that BK is an important modulating agent and enhances the immunological changes identified in transgenic neurospheres that carry the genetic load of AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE246792 | GEO | 2024/04/30

REPOSITORIES: GEO

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Project description:Extracellular senile plaques of amyloid beta (Abeta) are a pathological hallmark in brain of patients with Alzheimer`s Disease (AD). Abeta is generated by the amyloidogenic processing of the amyloid precursor protein (APP). Concomitant to Abeta load, AD brain is characterized by an increase in protein level and activity of the angiotensin-converting enzyme (ACE). ACE inhibitors are a widely used class of drugs with established benefits for patients with cardiovascular disease. However, the role of ACE and ACE inhibition in the development of Abeta plaques and the process of AD-related neurodegeneration is not clear since ACE was reported to degrade Abeta. To investigate the effect of ACE inhibition on AD-related pathomechanisms, we used Tg2576 mice with neuron-specific expression of APPSwe as AD model. From 12 months of age, substantial Abeta plaque load accumulates in the hippocampus of Tg2576 mice as a brain region, which is highly vulnerable to AD-related neurodegeneration. The effect of central ACE inhibition was studied by treatment of 12 month-old Tg2576 mice for six months with the brain penetrating ACE inhibitor captopril. At an age of 18 months, hippocampal gene expression profiling was performed of captopril-treated Tg2576 mice relative to untreated 18 month-old Tg2576 controls with high Abeta plaque load. As an additional control, we used 12 month-old Tg2576 mice with low Abeta plaque load. Whole genome microarray gene expression profiling revealed gene expression changes induced by the brain-penetrating ACE inhibitor captopril, which could reflect the neuro-regenerative potential of central ACE inhibition. Microarray gene expression profiling was performed of hippocampi isolated from aged, 18 month-old Tg2576 (APPSwe-transgenic) AD mice with high Abeta plaque load relative to age-matched Tg2576 mice, which were treated for 6 months with the centrally active ACE inhibitor captopril. Another study group consisted of 12 month-old Tg2576 mice with low Abeta plaque load. In total, three study groups were analyzed, i.e. (i) 18 month-old untreated Tg2576 mice with high Abeta plaque load, (ii) age-matched Tg2576 mice treated for 6 months with the brain-penetrating ACE inhibitor captopril (20 mg/kg body weight/day in drinking water), and (iii) untreated 12 month-old Tg2576 mice with low Abeta plaque load reflecting the time point when captopril treatment was initiated. Two biological replicates were made of each group, and total hippocampal RNA of four mice was pooled for one gene chip.

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Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APP swe and PS1 dE9 mutations

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