Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-specific neurodegenerative disease that compromises cognitive functioning and impacts the quality of life of an individual. Pathologically, AD is characterised by abnormal accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein. Despite research advances over the last few decades, there is currently still no cure for AD. Although, medications are available to control some behavioural symptoms and slow the disease's progression, most prescribed medications are based on cholinesterase inhibitors. Over the last decade, there has been increased attention towards novel drugs, targeting alternative neurotransmitter pathways, particularly those targeting serotonergic (5-HT) system. In this review, we focused on 5-HT receptor (5-HTR) mediated signalling and drugs that target these receptors. These pathways regulate key proteins and kinases such as GSK-3 that are associated with abnormal levels of Aβ and tau in AD. We then review computational studies related to 5-HT signalling pathways with the potential for providing deeper understanding of AD pathologies. In particular, we suggest that multiscale and multilevel modelling approaches could potentially provide new insights into AD mechanisms, and towards discovering novel 5-HTR based therapeutic targets.

Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer’s Disease

“…AKT phosphorylates and consequently inactivates glycogen synthase kinase-3 (GSK3) that phosphorylates tau protein. 5HTR 2 could modulate GSK3 phosphorylation through protein kinase C (PKC) [ 50 ] and β-arrestin-mediated signaling [ 51 ], while 5HTR 4 , 5HTR 6 , and 5HTR 7 could modulate GSK3 phosphorylation through protein kinase A (PKA) [ 50 ]. Several studies also observed an association between APOE and 5HT receptors.…”

Impact of different diagnostic measures on drug class association with dementia progression risk: a longitudinal prospective cohort study

“…While depression had an OR value of 1.32 (FDR p<0.001) suggesting that it is associated with increased risk of progression, however, treatment of the disorder with certain antidepressants can protect against this risk. Studies have suggested that SARIs like trazodone exhibit neuroprotective properties when examined in mammalian cell cultures and in neurodegenerative mouse models (Halliday et al, 2017) with complex cellular signalling pathway mechanisms (Joshi et al, 2020).…”

Modeling Neurotransmission: Computational Tools to Investigate Neurological Disorders

“…Multiscale and multilevel modelling approaches attempted to provide new insights into AD mechanisms and can be further expanded to identify novel therapeutic targets and pharmacological treatments such as the serotoninergic system, which has been deeply investigated through computational methods over the last decade [ 133 ].…”