Microglial Drug Targets in AD: Opportunities and Challenges in Drug Discovery and Development

Abstract

Alzheimer's disease (AD) is a large and increasing unmet medical need with no disease-modifying treatment currently available. Genetic evidence from genome-wide association studies (GWASs) and gene network analysis has 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 messenger RNA (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 peripheral 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 cluster of differentiation 33 (CD33), K_Ca3.1, kynurenines, ionotropic P2 receptor 7 (P2X7), programmed death-1 (PD-1), Toll-like receptors (TLRs), and triggering receptor expressed in myeloid cells 2 (TREM2).

Keywords: drug target; microglia; screening cascade; target identification; target validation.

Figure 1

Schematic representation of the preclinical drug discovery process. The preclinical drug discovery process can generally be divided into six unique steps from target identification to preclinical testing.

Figure 2

The proposed interplay between CD33 and TREM2 in microglial phagocytosis. CD33 and TREM2 have been proposed to be inhibitors or activators of microglial phagocytosis, respectively. For TREM2, activating antibodies, and for CD33, inhibitory antibodies, have been proposed as therapeutic interventions. Figure created with Biorender.com

Figure 3

The kynurenine pathway of tryptophan metabolism in the brain. Simplified diagram depicting the tryptophan–kynurenine pathway. Metabolism of tryptophan along the kynurenine pathway in the brain is regulated by a variety of enzymes that are largely segregated by cell type.

Figure 4

Schematic representation of microglial drug targets discussed in this review. This simplified schematic does not contain all signal transduction molecules known to be involved in the described signaling cascades but focuses on the microglial drug targets discussed in this review indicated by lighting bolts and antibody symbol. IDO, indolamine-2,3-dioxygenase; IL-1β, interleukin 1 beta; IL-18, interleukin 18; K_Ca3.1, intermediate-conductance calcium-activated potassium channel 3.1; KYN, kynurenine; AA, anthranilic acid; 3-HK, 3-hydroxykynurenine; KATs, kynurenine aminotransferases; KMO, kynurenine 3-monooxygenase (kynurenine 3-hydroxylase); NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain–containing inflammasome complex 3; P2X7, ionotropic P2 receptor 7; TIRAP, TIR domain–containing adaptor protein; MyD88, myeloid differentiation primary response protein 88; TDO, tryptophan-2,3-dioxygenase; TRP, tryptophan. Figure created with Biorender.com