A Critical Goal: Preventing Old Age Dementias

Normal Brain vs Alzheimer’s Dementia


What good is it to live a long and healthy life, if your brain turns to mush between the age of 65 and 75? May as well die at the age of 60, shot by a jealous husband while exiting a second story bedroom window. (If the bullet doesn’t get you, landing on your head on the concrete below will pay the final bill.)

Several explanations for most old age dementias — including Alzheimer’s — have failed to reach explanatory status. Current hypotheses for old age dementias are not good enough to generate effective methods of prevention or treatment.

Stanford researchers have now pointed the finger of blame for senile dementia at complement activator C1q. Levels of C1q are much higher in older animals’ brains, suggesting a link to neuronal degeneration of old age.

Topic315NotesImage4 C1q

C1q is a well-established component of what is known as the complement system – a group of 20 proteins that help antibodies and macrophages clear pathogens from the body. Considered the initiator of the system, C1q is responsible for recognizing the body’s “garbage,” such as bacteria, dying cells, and other harmful agents.

After locating these potentially dangerous cells, C1q binds to them and triggers a molecular reaction known as the amplifying cascade, in which the remaining 19 complement proteins bind to and coat the debris. This allows the macrophages (immune cells) to recognize the complement-tagged junk and eliminate it from the body.
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“In the body, this system makes a lot of sense,” Barres said. “All the cells in the body contain inhibitors to the complement, so normal cells aren’t targeted and destroyed. For example, a normal liver cell will be fine, so it doesn’t have to worry about showers of complement protein.”

It was previously thought that the complement system did not exist in the brain, but in 2007, Barres’ group discovered that this system is actually hard at work in the brains of infants. As a young brain grows, it generates an excess of synapses that will potentially form new neural circuits. However, since too many synapses are created, the brain had to develop a mechanism for eliminating the ones deemed unnecessary.

“The mystery was nobody knew how the extra synapses were removed,” Barres explained.

Through their research, they found that this synaptic pruning was done by the complement system. The microglia – the brain’s version of immune cells – were secreting C1q, while other brain cells called astrocytes were responsible for secreting the rest of the complement proteins. As a result, the microglia would then attack the complement coated synapses, eliminating the excess from the brain.

“This is what really got us interested,” Barres said. “Neurodegenerative disorders are well described as unwanted synapse degeneration. So there is massive synapse loss, but no one knows why. We thought maybe the complement system is way overactive in Alzheimer’s. It’s not normally active in the typical adult brain, but in Alzheimer’s, it turns on like a switch.” _Source

This is an amazing coincidence. The same process responsible for pruning the excess neurons of infancy, may also be responsible for eliminating the not-so-excess neurons of old age. If C1q builds up in the brains of the elderly, and cannot be eliminated, it will continue to target old age neurons until the lights go out.

Other researchers have been making a study of C1q inhibitors for several years, in an attempt to tame glaucoma. But a cure for senile dementia would have a much bigger impact in the scheme of things than a cure for glaucoma — as important as that may be.

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C1q inhibitors would likely be a first step holding action, while researchers learn to rejuvenate old neurons to look and work like new.

The great mountains of signaling cascades and the complexities of gene expression have barely been mapped, much less scaled.

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