31 Oct 2001

In Parkinson's disease, as in Alzheimer's, it remains unclear why only a subset of neurons is affected. A report in tomorrow's Journal of Neuroscience now suggests that, in PD, the reason for that specificity may lie in immune/inflammatory and oxidative processes initiated or amplified by activated microglial cells.

When activated, microglia secrete molecules including inflammatory cytokines, such as TNF-α, IL-1-β, INF-γ, and potentially toxic reactive oxygen species such as O₂^-, H₂O₂, and NO. Because inflammatory/immune activity and oxidative stress are pathological features of PD (and of AD), and also because activated microglia and their products have been detected in great quantity around dying substantia nigra dopaminergic (DA) neurons, some researchers have suggested that the microglia may play a role in the neurodegeneration. However, it is also possible that their role is entirely secondary, that the microglia are mopping up (phagocytosing debris) after the death of the DA cells.

To address these possibilities, Stanley Appel, Wei-dong Le, and colleagues at Baylor College of Medicine in Houston, Texas, have developed an in-vitro system of microglia and DA cells. They are able to activate the microglia with bacterial lipopolysaccharides, but also with a concoction of immunoglobulin-G (IgG) from PD patients combined with membrane fragments from DA neurons. This is relevant because PD IgG has been shown to kill DA cells when injected into rats. By contrast, membranes from cholinergic neurons did not activate the microglia.

Next, the researchers demonstrated that this system of activated microglia will injure cultured dopaminergic neurons, but not cholinergic or GABAergic ones. They can trace the damage to certain reactive oxygen species (in particular, H₂O₂ and NO) produced by the microglia. This activation requires the presence of the microglial Fc-γ-R receptor, to which IgG's bind.

With previous evidence, these results "provide potential mechanisms whereby the presence of modified dopaminergic cell membrane constituents in PD, in combination with PD IgG, could activate microglia and in turn amplify dopaminergic cell injury," write the authors.—Hakon Heimer