Alzheimer's disease: new therapeutic strategies
Over the past couple decades, researchers have identified numerous genes involved in various immune system functions that may also contribute to Alzheimer's.
Some of the prime suspects are genes that control immune cells called microglia.
Microglia are amoeba-like cells that scour the brain for injuries and invaders. They help clear dead or impaired brain cells and literally gobble up invading microbes.
In a normal brain, a protein called beta-amyloid is cleared away through our lymphatic system by microglia as molecular junk.
But sometimes it builds up. Certain gene mutations are one culprit in this toxic accumulation. Traumatic brain injury is another, and, perhaps, impaired microglial function.
Once amyloid begins to clog networks of neurons, it triggers the accumulation of another protein, called tau, inside of these brain cells. The presence of tau sends microglia and other immune mechanisms into overdrive, resulting in the inflammatory immune response that many experts believe ultimately saps brain vitality in Alzheimer's.
To date, nearly a dozen genes involved in immune and microglial function have been tied to Alzheimer's.
The first was CD33, identified in 2008. CD33 is a kind of microglial on-off switch, activating the cells as part of an inflammatory pathway.
Much of our modern human immune system, he explains, evolved many hundreds of thousands of years ago. Our lifespans at the time were far shorter than they are today, and the majority of people didn't live long enough to develop dementia or the withered brain cells that come with it. So our immune system, he says, assumes any faulty brain tissue is due to a microbe, not dementia. Microglia react aggressively, clearing the area to prevent the spread of infection.
If CD33 is the yin, a gene called TREM2 is the yang.
Discovered a few years after CD33, TREM2 reins in microglial activation, returning them to their role as cellular housekeepers.
The microglial activation in impending dementia as a double-edged sword. In the beginning, microglia clear unwanted amyloid to maintain brain health. But once accumulated amyloid and tau have done enough damage, the neuroinflammation that comes with microglial activation does more harm than good. Neurons die en masse and dementia sets in.
In theory, if a treatment could, say, decrease CD33 activity or increase that of TREM2, doctors might one day be able to slow or even stop the progression of dementia. Instead of going after amyloid itself ― the mechanism behind so many failed investigational Alzheimer's drugs ― a therapy that quells the immune response to amyloid might be the answer in treating dementia.