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

NEUROPHARMACOLOGY

卷:174

Review

Joshi, Alok¹  Wang, Da-Hui^2,3  Watterson, Steven⁴  McClean, Paula L.⁴  Behera, Chandan K.¹  Sharp, Trevor⁵  Wong-Lin, KongFatt¹ 

[1] Ulster Univ, Intelligent Syst Res Ctr, Northland Rd, Derry Londonderry BT48 7JL, North Ireland

[2] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China

[3] Beijing Normal Univ, Sch Syst Sci, Beijing, Peoples R China

[4] Ulster Univ, Biomed Sci Res Inst, Northern Ireland Ctr Stratified Med, Derry Londonderry, North Ireland

[5] Univ Oxford, Dept Pharmacol, Oxford, England

关键词: Alzheimer's disease;    Dementia;    Beta-amyloid;    Tau;    Serotonin;    Serotonin targeted drugs;    GSK-3;    Multiscale computational modelling;    Mechanistic models;    Boolean models;    Data-driven models;    Knowledge-driven models;   

DOI  :  10.1016/j.neuropharm.2020.108118

来源: Elsevier

【 摘 要 】

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 (A beta) 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 A beta 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.

【 授权许可】

Free