Viral involvement in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs). Initial memory impairment and cognitive decline are the most common symptoms in patients diagnosed with AD. After being diagnosed with AD, the patient will eventually lose the capacity to engage in daily activities such as eating and talking. Since AD was discovered 100 years ago, there has been no effective cure for this disease. The ability to develop a successful cure is exceptionally challenging due to the complexity of the disease and the diversity of the risk factors. Many clinical trials have failed to create the optimal drug to treat AD. The pathology of this disease is broad and complex and microbial pathogens have started to gain more attention from the scientific field. Many microbial pathogens could be related to the pathology of AD. For example, herpes simplex virus-1 (HSV-1) is one of the most cited candidates linked to AD for various reasons, including the discovery of HSV-1 in the postmortem brains of Alzheimer's patients. In addition, HSV-1 can lead to the accumulation of Aβ and NFTs in an animal model of AD. Therefore, to investigate the possible involvement of HSV-1 in AD pathology, the use of differentiated SH-SY5Y cells as a neuronal model for the study was applied. SH-SY5Y is a neuroblastoma cancer cell line that can differentiate into neurons when treated with retinoic acid (RA). The exposure of SH-SY5Y cells to RA for 3 days led to increased neurite lengths and enhanced the expression of many neuronal biomarkers, including nerve growth factor (NGF), choline acetyltransferase (ChAT), dopamine receptors type 2 (DRD2), and tubulin beta 3 (TUBB3). To investigate the role of HSV-1 and Aβ 42 in AD pathogenesis, multiple comparisons were made against the control (differentiated SH-SY5Y cells), including, 1) differentiated SH-SY5Y cells co-cultured with Aβ 42, 2) differentiated SH-SY5Y cells co-cultured with HSV-1, 3) differentiated SH-SY5Y cells co-cultured with Aβ 42 and HSV-1. The bioinformatics analysis using ingenuity pathway analysis (IPA) was applied to all groups of comparisons. The first comparison exhibited a significant enrichment in the neuroinflammation pathway. The second comparison indicated that the kinetochore metaphase signalling pathway was activated. The third comparison showed enrichment of the tumour microenvironment pathway. The previous comparisons were inadequate to evaluate the impact of HSV-1 and Aβ 42 on differentiated SH-SY5Y cells since they did not demonstrate the effects of Aβ 42 when HSV-1 is present and the effects of HSV-1 when Aβ 42 is present. Therefore, treated groups (SH-SY5Y cells co-cultured with Aβ 42, SH-SY5Y cells co-cultured with HSV-1, SH-SY5Y cells co-cultured with Aβ 42 and HSV-1) were also compared to each other rather than just the controls (differentiated SH-SY5Y cells). The outcomes show that Aβ 42 and HSV-1 in differentiated SH-SY5Y cells stimulated the activation of genes that were not associated with the AD phenotype but were possibly connected to early development, genetic disorders, and cancer. In addition, among the pool of 20 differentially expressed genes, a noteworthy finding emerged. 10 of the differentially expressed genes identified to be positioned on chromosome 1. This interesting observation could potentially be attributed to the malignant characteristics of SH-SY5Y cells, which exhibits trisomy, resulting in an additional copy of the q arm on chromosome 1. The addition of Aβ 42 and HSV-1 to differentiated SH-SY5Y cells resulted in the initiation of a malignant phenotype rather than AD. Using a more advanced model that accurately represents AD could be a preferable option for studying the connection between HSV-1 and AD.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Doig (Supervisor) & Philip Day (Supervisor)