Journal Article

The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer’s disease

Spencer, Sarah J., Slayo, Mary, Rummel, Christoph, Singhaarachchi, Pasindu Hansana, Feldotto, Martin

2025

Overview

Alzheimer’s disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β may play a key role. Microglia are the major innate immune cell of the central nervous system and are critical responders to pro-inflammatory states. Typically, microglia react with a short-lived inflammatory response. However, a dysregulation in the resolution of this microglial response results in the chronic release of inflammatory mediators. This prolongs the state of neuroinflammation, likely contributing to the pathogenesis of AD. In addition, the microglial specialised pro-resolving mediator (SPM) contribution to phagocytosis of amyloid-β is dysregulated in AD. SPMs are derivatives of dietary n-3 polyunsaturated fatty acids (PUFAs) and potentially represent a strategic target for protection against AD progression. However, there is little understanding of how mitochondrial respiration in microglia may be sustained long term by n-3-derived SPMs, and how this affects their clearance of amyloid-β. Here, we re-evaluate the current literature on SPMs in AD and propose that SPMs may improve phagocytosis of amyloid-β by microglia as a result of sustained mitochondrial respiration and allowing a pro-resolution response.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine triphosphate / Advertising executives / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Animals / Beta-oxidation / Bioenergetics / Biomedical and Life Sciences / Biomedicine / Brain / Brain research / Cell Respiration - physiology / Central nervous system / Dementia disorders / Development and progression / Disease / Fatty acids / Fatty Acids, Omega-3 - metabolism / Gene expression / Genotype & phenotype / Humans / Immune clearance / Inflammation / Inflammation - metabolism / Kinases / Lipids / Metabolism / Metabolites / Microglia / Microglia - metabolism / Mitochondria / Mitochondria - metabolism / Molecular Medicine / Neurodegenerative diseases / Neurofibrillary tangles / Neurology / Neuropathology / Neurosciences / Parkinson's disease / Pathology / Peptides / Phagocytosis / Phagocytosis - physiology / Phosphorylation / Polyunsaturated fatty acids / Proteins / Reactive oxygen species / Respiration / Review / Target marketing / Tau protein / Unsaturated fatty acids / β-Amyloid