Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α-synuclein, amyloid-β and insulin resistance in neurodegenerative diseases

Abstract

While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non-infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α-synuclein, amyloid-β levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti-TNF agent, on α-synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti-TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti-TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states.

Figure 1

An illustration of how a range of chronic external stimuli that present DAMPs or PAMPs to various TLRs on different cerebral cellular components and thus induce TNF and similar cytokines. These in turn generate P‐tau, α‐synuclein (α‐Syn) and Aβ, proteins known to have the capacity to be secondary DAMPs (i.e. induced by TNF, and also act as a TLR agonist, thereby inducing more TNF). Clinical manifestations and therefore diagnoses vary, but the broad edifice, we argue, rests on a foundation of chronic pro‐inflammatory cytokines generated in this manner.

Figure 2

A visual comparison of complexity of methods designed to generate similar clinical improvements in post‐stroke syndromes by reducing cerebral TNF. To date, both have been done in open trials only. Illustration adapted from ‘Head anatomy anterior lateral views’; Patrick J. Lynch; illustrator; C. Carl Jaffe; MD; cardiologist Yale University Center for Advanced Instructional Media; Creative Commons Attribution 2.5 Licence 2006.