Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease.
The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer's disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients' cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer's disease, and the treatment approaches they provide. A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.
Research School of Biology, Australian National University, Canberra, Australia. Electronic address: ian.clark@anu.edu.au.
Ian A
IA
Clark
Bryce
B
Vissel
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007251:Influenza, Human / Q000150:complications / Q000503:physiopathology; D007333:Insulin Resistance; D007854:Lead / Q000633:toxicity; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D022661:RNA, Untranslated; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D016207:Cytokines; D022661:RNA, Untranslated; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051844:alpha-Synuclein; D007854:Lead
Alzheimer's disease; DNA hypomethylation; Insulin resistance; Parkinson's disease, α-Synuclein; TNF