Microglia: A pharmacological target for the treatment of age-related cognitive decline and Alzheimer’s disease

Abstract

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer’s disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS. Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress. Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

Neuroprotective Mechanisms of Salidroside in Alzheimer’s Disease: A Systematic Review and Meta-analysis of Preclinical Studies

“…55 Therefore, mitigating this dysfunction is the most critical factor in determining the effectiveness of potential drug modeling and treatment efficacy. 56 A total of 20 studies were included in this meta-analysis performing multiple behavioral tests to evaluate the learning and memory functions of AD animal models. These tests included MWM, passive avoidance tests, Y-maze tests, OFT experiments, and novel object recognition (NOR) experiments.…”

“…The most characteristic manifestation of AD is cognitive and memory decline . Therefore, mitigating this dysfunction is the most critical factor in determining the effectiveness of potential drug modeling and treatment efficacy . A total of 20 studies were included in this meta-analysis performing multiple behavioral tests to evaluate the learning and memory functions of AD animal models.…”

Neuroprotective Effects of Leptin on the APP/PS1 Alzheimer’s Disease Mouse Model: Role of Microglial and Neuroinflammation

“… 55 In general, moderate rises in these cytokines have been identified as a natural aspect of aging. 8 , 56 However, significant elevations, as seen in AD, result in excessive neurotoxicity, which fuels the neurodegenerative process and, as a result, may be related to the pathology of AD. 57 In disorders of the brain, severe neuronal damage can cause chronic activation that results in the persistent produce of pro-inflammatory chemicals and the damaging generation of ROS, both of which have negative effects.…”

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures

“…Vinculin was used as a normalising control. Description of the arrangement of the samples (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…Microglia, the brain's resident immune cells, play a crucial role in health and disease [1,2]. They defend the brain against infections and injury [3], contribute to neurogenesis and synaptic conditions, and interact with neurons and other brain cells to control homeostasis [4][5][6][7]. Importantly, microglial cells are susceptible to the surrounding environment [8] and possess various receptors to sense microenvironment changes that regulate their functions [9,10].…”