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), KCa3.1, kynurenines, ionotropic P2 receptor 7 (P2X7), programmed death-1 (PD-1), Toll-like receptors (TLRs), and triggering receptor expressed in myeloid cells 2 (TREM2).
Highlights
Microglial reactivity has long been recognized as a pathological hallmark of a wide variety of neurological diseases
We will review some commonly suggested microglial targets and pathways, i.e., cluster of differentiation 33 (CD33), KCa3.1, kynurenines (KYN), ionotropic P2 receptor 7 (P2X7), programmed death-1 (PD-1), Toll-like receptors (TLRs), and triggering receptor expressed in myeloid cells 2 (TREM2), discussing their potential role in AD and their respective challenges in regard to drug discovery
CD33-deficient Amyloid precursor protein (APP)/ Presenilin 1 (PS1) mice showed reduced amyloid pathology compared to age-matched wildtype (WT) controls, supporting the idea that reduced microglial CD33 function is beneficial with respect to amyloid pathology (Griciuc et al, 2013)
Summary
Microglial reactivity has long been recognized as a pathological hallmark of a wide variety of neurological diseases. Using the search term “microglia Alzheimer,” PubMed lists close to 100 reviews that were published in the last 2 years (Jan 2017–Jan 2019). It is not the purpose of the current review to discuss the potential role of microglia in AD, but to focus on the challenges and practical aspects of microglial proteins or pathways as potential drug targets. We will review some commonly suggested microglial targets and pathways, i.e., cluster of differentiation 33 (CD33), KCa3.1, kynurenines (KYN), ionotropic P2 receptor 7 (P2X7), programmed death-1 (PD-1), Toll-like receptors (TLRs), and triggering receptor expressed in myeloid cells 2 (TREM2), discussing their potential role in AD and their respective challenges in regard to drug discovery
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