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Tumor necrosis factor-induced cerebral insulin resistance in alzheimer's disease links numerous treatment rationales


The evident limitations of the amyloid theory of the pathogenesis of Alzheimer?s disease are increasingly putting alternatives in the spotlight. We argue here that six independently developing approaches to therapy ? suppression of gonadotropin signalling (leuprolide acetate), specific and non-specific anti-TNF agents, leptin, intranasal insulin, the GLP-1 mimetics and GSK-3 antagonists ? rationalize an interlocking chain of events. These include aberrant cell cycle signalling and cell degeneration, subsequent inflammation and thence cerebral insulin resistance, being the pathway on which to focus for a successful clinical outcome in treating this disease. A key link in this chain presently absent from the literature is a recognition by Alzheimer?s researchers of the long-neglected history of TNF, which has recently been realized to be modulated by gonadotropins, inducing insulin resistance. When this is incorporated into the bigger picture it becomes evident that these six interventions are not competing alternatives, but equally valid approaches to correcting different parts of the same pathway to Alzheimer?s disease. They can be expected to be at least additive, and conceivably synergistic, in effect. In summary, the gonadotropin, inflammation, leptin, insulin resistance, GSK-3 and mitochondrial dysfunction hypotheses are not opposing ideas but sequential stages of the same fundamental, overarching, pathway of Alzheimer?s disease pathogenesis. The insight this provides into adult neurogenesis, and thus repair, is a key part of this approach. This pathway also has therapeutic implications for other circumstances in which brain TNF is pathologically increased, such as stroke, traumatic brain injury, and the infectious disease encephalopathies.

Type Journal
Authors Clark, I.; Atwood, C.; Bowen, R.; Paz-Filho, G.; Vissel, B.
Garvan Authors Dr Bryce Vissel
Publisher Name PHARMACOL REV
Published Date 2012-09-12 00:00:00
Published Volume 64
Published Issue 4
Published Pages 1004-26
Status Published In-print
OpenAccess Link Clark Pharmacol Rev_ C1.pdf