title: A state of delirium: Deciphering the effect of inflammation on tau pathology in Alzheimer's disease.
abstract: Alzheimer's disease (AD), the predominant form of dementia, is highly correlated with the abnormal hyperphosphorylation and aggregation of tau. Immune responses are key drivers of AD and how they contribute to tau pathology in human disease remains largely unknown. This review summarises current knowledge on the association between inflammatory processes and tau pathology. While, preclinical evidence suggests that inflammation can indeed induce tau hyperphosphorylation at both pre- and post-tangles epitopes, a better understanding of whether this develops into advanced pathological features such as neurofibrillary tangles is needed. Microglial cells, the immune phagocytes in the central nervous system, appear to play a key role in regulating tau pathology, but the underlying mechanisms are not fully understood. Their activation can be detrimental via the secretion of pro-inflammatory mediators, particularly interleukin-1β, but also potentially beneficial through phagocytosis of extracellular toxic tau oligomers. Nevertheless, anti-inflammatory treatments in animal models were found protective, but whether or not they affect microglial phagocytosis of tau species is unknown. However, one major challenge to our understanding of the role of inflammation in the progression of tau pathology is the preclinical models used to address this question. They mostly rely on the use of septic doses of lipopolysaccharide that do not reflect the inflammatory conditions experienced AD patients, questioning whether the impact of inflammation on tau pathology in these models is dose-dependent and relevant to the human disease. The use of more translational models of inflammation corroborated with verification in clinical investigations are necessary to progress our understanding of the interplay between inflammation and tau pathology.
authors.affiliation: School of Life sciences, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Barron
authors.affiliation: Eisai Inc., 4 Corporate Drive, Andover, MA 01810, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Gartlon
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park Rd, Cambridge CB4 0QA, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.affiliation: Eisai Ltd., EMEA Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Atkinson
authors.affiliation: School of Life sciences, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK. Electronic address: marie.pardon@nottingham.ac.uk.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Pardon
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D016875:tau Proteins
keywords: Alzheimer's disease; Inflammation; Lipopolysaccharide; Phosphorylation; Preclinical models; Tau