It can't be coincidental that the substantia nigra contains the most microglia.

Nature Reviews Neuroscience 8, 57-69 (January 2007) | doi:10.1038/nrn2038
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

Michelle L. Block1, Luigi Zecca2 and Jau-Shyong Hong1

Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.



For many years, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease have been a major focus of neuroscience research, with much effort being devoted to understanding the cellular changes that underlie their pathology. Microglia, the resident innate immune cells in the brain, have been implicated as active contributors to neuron damage in neurodegenerative diseases, in which the overactivation and dysregulation of microglia might result in disastrous and progressive neurotoxic consequences. Although these concepts have been widely reviewed in recent years1, 2, 3, the characteristics defining deleterious microglial activation and the mechanisms by which neurotoxic microglial activation is initiated remain poorly understood. In the current review, we therefore focus on recent reports indicating that pattern recognition receptors (PRRs) are tools used by microglia to identify neurotoxic stimuli and that stimulation of NADPH oxidase activity is the predominant mechanism through which microglia produce neurotoxic reactive oxygen species (ROS). We further explain how the identification of these crucial participants in microglia-mediated neuronal injury could provide the insight necessary for the development of novel markers that specifically define deleterious microglial activation. Furthermore, these mechanisms might be ideal prospects for targeted anti-inflammatory therapy capable of slowing and perhaps preventing neurodegenerative diseases.

Microglia: friend and foe

........In the mature brain, microglia typically exist in a resting state characterized by ramified morphology, and monitor the brain environment7, 8. In response to certain cues such as brain injury or immunological stimuli, however, microglia are readily activated7, 9. Activated microglia undergo a dramatic transformation from their resting ramified state into an amoeboid morphology and present an upregulated catalogue of surface molecules.......


....Activated microglia are involved in regulating brain development by enforcing the programmed elimination of neural cells19, 20, and seem to enhance neuronal survival through the release of trophic and anti-inflammatory factors21, 22, 23. In addition, in the mature brain, microglia facilitate repair through the guided migration of stem cells to the site of inflammation and injury24, and might be involved in neurogenesis......

Under other circumstances, however, microglia become overactivated and can induce significant and highly detrimental neurotoxic effects by the excess production of a large array of cytotoxic factors such as superoxide29, nitric oxide (NO)30, 31 and tumour necrosis factor-alpha (TNFalpha)32, 33. The stimuli that cause microglial overactivation and dysregulation can be diverse, ranging from environmental toxins, such as the pesticide rotenone, to neuronal death or damage. In neurodegenerative disease, activated microglia have been shown to be present in large numbers, a condition termed microgliosis, strongly implicating these cells in disease pathology.

Currently, the conditions defining whether microglial activation is detrimental or beneficial to neuronal survival are poorly understood. However, it is becoming more widely accepted that although microglial activation is necessary and crucial for host defence and neuron survival, the overactivation of microglia results in deleterious and neurotoxic consequences26. It is because of this that understanding the causes and defining the characteristics of deleterious microglial activation in neurodegenerative disease has become a recent focus of research......

re: PD...

Microglial activation in this disease is not limited to the substantia nigra, but is also found in the putamen, hippocampus, transentorhinal cortex, cingulate cortex and temporal cortex51.

The selective loss of DA neurons in the substantia nigra might be due to DA neuron glutathione deficiency52 (resulting in a reduced antioxidant capacity), high content of DA (a redox active molecule) in neurons in the substantia nigra53, elevated iron concentrations54 (redox active elements) and increased numbers of microglia in the substantia nigra6, 55 compared with other regions.

So, DA neurons in the substantia nigra might be particularly vulnerable to inflammatory insult owing to their precarious redox equilibrium and colocalization with a large population of microglia.....

Several in vitro studies reveal that damaged DA neurons release several factors that seem to activate microglia and are implicated in neuronal degeneration in Parkinson's disease......

Neuromelanin is a complex molecule made of melanin, peptides and lipid components that is released in Parkinson's disease by dying DA neurons to activate microglia59. Neuromelanin is insoluble and so remains for an extended time in the extracellular space, is loaded with toxins able to activate microglia, and is localized at high concentrations in the human substantia nigra (2–4 mg g-1 tissue)59. Human neuromelanin added to neuron–glia cultures is phagocytosed and degraded by microglia with the release of inflammatory factors and ROS, which lead to neuronal death60 (L.Z., unpublished observations). So, neuromelanin seems to be a potential candidate for the establishment of the perpetuating cycle of reactive microgliosis in Parkinson's disease.

.....Microglia, inflammation and neurotoxicity.

As discussed above, microglia-mediated neurotoxicity tends to be progressive97, 98, 99, which could contribute to the progressive nature of several neurodegenerative diseases.

This has been most effectively demonstrated in models using lipopolysaccharide (LPS), the polysaccharide component of the cell walls of gram-negative bacteria. Although LPS models cannot not precisely mimic the conditions under which microglia are activated in neurodegenerative disease, these studies demonstrate that LPS is neurotoxic only in the presence of microglia, indicating that microglia can initiate neuronal damage100, 101.

For example, LPS is reported to induce microglial activation in vivo and in vitro and cause the progressive and cumulative loss of DA neurons over time100, 102, 103. Furthermore, embryonic exposure to LPS has an impact on microglial activation and neuron survival into adulthood103, 104. Interestingly, once overactivated, microglia can remain in this state, as evidenced by the chronic neuroinflammation that continues years after brief MPTP exposure in humans50 and primates98.

http://www.nature.com/nrn/journal/v8...l/nrn2038.html

Fortunately, endogenous protective regulatory signals in the brain have been identified that inhibit microglial overactivation, such as neuropeptides121, 122, 123, cannabinoids124, 125, anti-inflammatory cytokines (that is, IL-10 and transforming growth factor-beta (TGFbeta))126, 127, oestrogen128, glucocorticoids129, 130, 131 and even microglial apoptosis132, 133. However, it has been proposed that when the ability to activate these protective mechanisms fails, or when they are overwhelmed by an excessive inflammatory response, microglia initiate neuronal death and drive the progressive nature of neurodegenerative disease26, 121. A full understanding of the mechanisms underlying microglial dysregulation and overactivation is of pressing interest because of the valuable insight it will provide into the aetiology, pathogenesis and treatment of neurodegenerative diseases.

So, microglial activation is present in diverse neurodegenerative diseases and is closely associated with pathology. Previously, the microglial response to neuronal damage was believed to be passive. However, recent reports indicate that microglial activation is capable of both initiating additional neuronal loss and amplifying ongoing neuronal damage, indicating that microglia might be crucial to the aetiology and the progressive nature of neurodegenerative diseases. Current work is therefore beginning to focus on the stimuli necessary to initiate deleterious microglial function, where studies have revealed several triggers of inflammation-mediated neurodegeneration are present in the environment.....