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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00840

Microglial drug targets in AD: opportunities and challenges in drug discovery and development.

Knut Biber1*,  Anindya Bhattacharya2,  Brian Campbell3,  Justin Piro4, Micheal Rohe1,  Roland Staal5, Robert Talanian4 and  Thomas Moeller4*
  • 1AbbVie (Germany), Germany
  • 2Janssen Neuroscience Research & Development, United States
  • 3SAGE Therapeutics, United States
  • 4AbbVie Foundational Neuroscience Center, United States
  • 5Paracelsus Neuroscience LLC, United States

Alzheimer’s disease (AD) is an increasing burden to society and healthcare systems, and one of the biggest unmet medical needs with no disease-modifying treatment. Genetic evidence from genome wide association (GWAS) studies and gene network analysis have clearly revealed a key role of the innate immune system in the brain, of which microglia are the most important element. ‘Single nucleotide polymorphisms (SNPs) in genes predominantly expressed in microglia have been associated with altered risk of developing AD. Furthermore, microglia-specific pathways are affected on the mRNA expression level in post-mortem AD tissue and in mouse models of AD. Together these findings have increased the interest in microglia biology, and numerous scientific reports have proposed microglial molecules and pathways as drug targets for AD. Target identification and validation are generally the first steps in drug discovery. Both target validation and drug lead identification for central nervous system (CNS) targets and diseases entail additional significant obstacles compared to peripherally restricted targets and diseases. This makes CNS drug discovery, even with well-validated targets, challenging. In this article, we will illustrate the special challenges of AD drug discovery by discussing the viability/practicality of possible microglia drug targets including CD33, Kca3.1, Kynurenines, P2X7, PD1, TLRs, and TREM2.

Keywords: drug target, Microglia, Target identification, target valisdation, Microglia receptors

Received: 14 Mar 2019; Accepted: 01 Jul 2019.

Edited by:

Pietro Giusti, University of Padova, Italy

Reviewed by:

Anthony J. Hannan, Florey Institute of Neuroscience and Mental Health, Australia
Claes Wahlestedt, Leonard M. Miller School of Medicine, United States  

Copyright: © 2019 Biber, Bhattacharya, Campbell, Piro, Rohe, Staal, Talanian and Moeller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Knut Biber, AbbVie (Germany), Wiesbaden, Rhineland-Palatinate, Germany,
Prof. Thomas Moeller, AbbVie Foundational Neuroscience Center, Cambridge, Maryland, United States,