Abstract
Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.
Highlights
We suggest that future studies should focus on targeted manipulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation
It is crucial to enhance NOX activation at the cellular level in these in vivo models of Alzheimer’s disease (AD). These findings strongly suggest a specific role for NADPH oxidase 2 (NOX2) activation in microglia associated with cerebral amyloid pathology
Molecular pathways in microglia contributing to neurodegeneration undoubtedly involve inflammatory-mediated reactive oxygen species (ROS) production by activation of NOX
Summary
Neurodegenerative diseases are characterised by an excessive and pathological loss of neurones that result in dementia, cognitive impairment, perturbed motor control and, death Due to their debilitating nature and lack of any effective treatment, neurodegenerative diseases are a growing economic burden to society [1]. Microglia often referred to as “brain-resident macrophages” are complex and dynamic mediators of neuroinflammation These phagocytic glia form a heterogeneous network that influences development, maintains homeostasis, surveys the parenchyma and reacts to damageand pathogen-associated stimuli [9,10]. Activated microglia promote tau phosphorylation and aggregation by activation of the NLRP3 (nucleotide binding oligomerisation domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3) inflammasome in response to amyloid-β [22,23] This identifies a mechanistic link between microglial activation in AD and the development of tau pathology. Identifying key molecular targets underlying changes to microglial physiology will be critical to developing neuroimmune modulatory therapies
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