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

Alok Joshi, Da-Hui Wang, Steven Watterson, Paula McClean, Chandan Behera, Trevor Sharp, KongFatt Wong-Lin

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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.

Original languageEnglish
Article number108118
JournalNeuropharmacology
Volume174
Early online date4 May 2020
DOIs
Publication statusPublished - 1 Sep 2020

Bibliographical note

Funding Information:
This work was supported by the Alzheimer's Research UK (ARUK) Pump Priming Award ( ARUK-2017NC-NI ) (A.J., D.-H.W., S.W., P.L.M., T.S. and K.W.-L.), BBSRC ( BB/P003427/1 ) (A.J., T.S., C.K.B. and K.W.-L.), Ulster University Research Challenge Fund (C.K.B., P.L.M. and K.W.-L.), NSFC ( 31671077 ) (D.-H.W) and European Union’s INTERREG VA Programme , managed by the Special EU Programmes Body (SEUPB (Centre for Personalised Medicine, IVA 5036)) (P. L.M. and K.W.-L.). K.W.-L. and S.W. were supported by COST Action (CA15120) Open Multiscale Systems Medicine (OpenMultiMed) supported by COST (European Cooperation in Science and Technology) . K.W.-L. was additionally supported by the Northern Ireland Functional Brain Mapping Project ( 1303/101154803 ) funded by Invest NI and Ulster University . The views and opinions expressed in this paper do not necessarily reflect those of the European Commission or the Special EU Programmes Body (SEUPB).

Funding Information:
This work was supported by the Alzheimer's Research UK (ARUK) Pump Priming Award (ARUK-2017NC-NI) (A.J. D.-H.W. S.W. P.L.M. T.S. and K.W.-L.), BBSRC (BB/P003427/1) (A.J. T.S. C.K.B. and K.W.-L.), Ulster University Research Challenge Fund (C.K.B. P.L.M. and K.W.-L.), NSFC (31671077) (D.-H.W) and European Union's INTERREG VA Programme, managed by the Special EU Programmes Body (SEUPB (Centre for Personalised Medicine, IVA 5036)) (P. L.M. and K.W.-L.). K.W.-L. and S.W. were supported by COST Action (CA15120) Open Multiscale Systems Medicine (OpenMultiMed) supported by COST (European Cooperation in Science and Technology). K.W.-L. was additionally supported by the Northern Ireland Functional Brain Mapping Project (1303/101154803) funded by Invest NI and Ulster University. The views and opinions expressed in this paper do not necessarily reflect those of the European Commission or the Special EU Programmes Body (SEUPB).

Publisher Copyright:
© 2020

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Alzheimer's disease
  • Dementia
  • Beta-amyloid
  • Tau
  • Serotonin
  • Serotonin targeted drugs
  • GSK-3
  • Multiscale computational modelling
  • Mechanistic models
  • Boolean models
  • Data-driven models
  • Knowledge-drivenmodels

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