Chronic inflammatory reactions are present in most age-related neurodegenerative disorders, including Alzheimer's disease (AD).
Over many years, a protein called amyloid beta forms sticky plaques in the brains of people with AD, ultimately killing the surrounding neurons and causing memory loss and other cognitive problems.
Inflammation or excessive action of the brain's immune cells (called glial cells) is another hallmark of the disease. Researchers generally have assumed that inflammation equates with injury and toxicity to neurons, but the relationship between glial cells, neurons and amyloid plaques remains unclear.
Inflammatory mediators released by glial cells can be directly toxic to neurons and therefore have been implicated as mediators of neurodegeneration. In AD, it has been hypothesized that these inflammatory cytokines can potentially promote further Abeta plaque accumulation.
We have now generated a wealth of data showing that over-expression of inflammatory cytokines (e.g., IL-6, IFNgamma and TNFalpha) does not increase Abeta plaque generation. Instead, these inflammatory cytokines significantly "prevent" amyloid deposition in mice. As opposed to the pro-inflammatory cytokines, recent data using AAV mediated expression of anti-inflammatory cytokines significantly increased amyloid plaque loads.
Based on this data and data generated by others, we hypothesize that depending on the timing and context, the actions of individual cytokines/chemokines may produce divergent and unexpected effects during the disease process, but it may possible to harness these immuno-modulatory effects to beneficially alter the AD phenotype.
Our studies will provide valuable insight into how neuro-inflammatory and imuno-modulatory reactions affect amyloid deposition and tau protein dysfunction, the two hallmark pathological features of AD.