If we just want to know how microglia relate to PD, it doesn't have to be that hard. <Gross oversimplification alert!>

Microglia are the immune system's warriors within the brain. Normally they are mild, milk toasty type that wouldn't harm a flea. But when called to action ("activated") they change. Ever see the TV show "The Incredible Hulk"? An activated microglial cell is like that only more so. Imagine a tiny T Rex.

They are part of the "First Responder" segment of our defenses. At the first scent of trouble, they hit the ground running and hold the fort while the rest of the immune system determines the nature of the invader, consults its library of past encounters, and mixes up a custom cocktail just for that particular pathogen. Meanwhile, the microglia are stomping on anything that doesn't have the proper ID.

Once the rest of the troops start arriving, the microglia are relieved of duty and can relax. Unfortunately for us, in PD those stand down orders are not received. It's not that they attack neurons by mistake (autoimmune response) but rather that they produce a cocktail that eventually wears out neurons (autotoxic response). T Rex is not attacking the village but he is pooping everywhere and after twenty years of this it becomes a problem.

What sets this in motion? Several things can do it and it depends on the individual. One is the bacterial toxin lipopolysacharide (LPS). LPS is everywhere and is so common that the body monitors its levels as an early warning system. But we each have different settings on how much will set off the alarms. If we encounter LPS in the womb, we can be very sensitive to it. If we have the flu, our sensitivity can be increased. That sensitivity determines how difficult it is to control the microglia.

They exposed a rat to LPS in the womb. Then they exposed the adult to LPS. The immune system revved up and within a few hours everything was back to normal outside the brain. But, within the BBB, the microglia remained in Hulk mode. In fact, they were still stomping around *ten months* later with a lot of dead neurons lying around. All from a single exposure.

The microglia get more touchy as we age. PD increases too. The substantia nigra has one of the highest densities of microglia in the brain.

A few week ago, I ran across an interesting tie between this and our neuroimmune-endocrine tangle. The orders to calm down are sent from the nervous system to the immune which then sends the orders out by means of specialized T cells. These T cells are sensitive to endocrine stress responses. In fact, trauma can cut their numbers in half. So, we have microglia ready to leap into action while headquarters keeps sending orders to desist but the number of couriers is falling. There's more here.