The Immune Cells of the Brain
(And What They Do During Alzheimer’s)
In Alzheimer’s disease, the brain’s neurons — cells that send electrical signals to each other — die progressively, leading to deficits in memory and cognition. However, these messaging neurons only make up about half of all the cells in the brain.
The other half of the brain’s cells are called glial cells. Glial cells are support cells that fight against any potential pathogens and patch up any damage that occurs. The two types of glial cells are called astrocytes and microglia. In a healthy brain, these cells are like gardeners, while your brain is their garden.
Proud gardeners tend to their plants, cutting off any dead leaves and preventing pests like squirrels from eating them. They watch over new seedlings to ensure that they sprout and grow, providing nourishment along the way. In the same way, the astrocytes and microglia in your brain provide nourishment and support so that your brain cells can grow. The astrocytes and microglia also get rid of any waste and protect against pathogens.
As the brain ages, the astrocytes and microglia continue to maintain the brain. After all, if you neglect your garden, weeds and pests will overtake it. They continue to clear debris and get rid of damaged cells, the same way you might decide to pull out a dead or dying plant from your garden. In this way, the glial cells are the immune system of the brain. After helping grow and sculpt the connections between brain cells, they now watch over this garden and protect it.
Alzheimer’s disease is marked by the buildup of two types of proteins in the brain called amyloid and tau. As these proteins accumulate, they form plaques and tangles and can drive too much inflammation, making the pathology worse. But glial cells may be able to help clear these plaques, if they can be stimulated to put their gardening skills to use.
Currently, there are no FDA-approved drugs that target the glial cells to stimulate the removal of amyloid plaques. However, in recent years, advances in research have made the brain’s immune system a viable therapeutic target.
Astrocytes in Alzheimer’s Disease
Astrocytes are star-shaped sentry and support cell6s in the brain serving many critical roles — acting as your brain’s head gardener. They help provide nutrients and factors that keep brain cells healthy and regulate their metabolism and functions. Additionally, when an astrocyte senses damage, it changes its shape and prepares an inflammatory response — the equivalent would be a gardener preparing to chase away a squirrel munching on their vegetables.
When an astrocyte responds to damage and prepares to clear debris, it becomes “activated”. Several studies have shown that astrocytes are activated before the onset of amyloid and tau pathology in rodent models and astrocytes are now being studied to understand if they can play a neuroprotective role in the brain.
In humans, astrocytes change their shape — characteristic of a special type of active state — near these amyloid and tau plaques. Activated astrocytes may signal alerts to another type of glial cell — the microglia — to help clear the amyloid and tau buildup. If we can control these “gardeners”, we could activate astrocytes so they clear these plaques.
Microglia in Alzheimer’s Disease
Microglia, as the name suggests, are small immune cells in the brain, and they can quickly mobilize in response to signals from astrocytes, disease, and pathogens. When they’re activated, microglia become much larger and rounder, as they prepare to engulf pathogens or cellular debris.
In the brains of people with Alzheimer’s disease, specific molecular markers of microglia activation were elevated in certain signals. Some researchers believe that they aren’t able to clear these plaques because the chemical signals they release in response to amyloid proteins will eventually slow their ability to digest and clear them.
In rodents, stimulating the microglia could even increase amyloid plaques. However, it is much more challenging to stimulate the microglia to selectively clear these amyloid plaques. Nonetheless, a drug called sodium oligomannate — which is derived from seaweed and currently in Phase 3 Alzheimer’s trials in the USA — is being tested in clinical trials to understand if remodeling certain immune interactions can lead to a reduction in microglial activation in the brain.
However, not all activated microglia harm the brain, and they could be harnessed to clear plaques. Cognito Therapeutics is entering Phase 3 trials with its neuro-modulation devices, which use sensory stimuli like flickering lights and sounds to activate microglia and induce the clearance of amyloid and tau plaques.
Targeting microglia and astrocytes may soon provide a novel disease-modifying approach for treating Alzheimer’s, but there is a certain “Goldilocks” problem that drug developers face when targeting glial cells — both too much and too little inflammation can be harmful.
Still, the acceleration of research in this space is a catalyst for new drugs and technology that may one day find a way to modify the course of Alzheimer’s with just the right amount of immune activation in the brain.
To learn about joining a clinical research study for Alzheimer’s disease, call Charter Research now at 352-775-1000 (The Villages) or 407-337-1000 (Orlando).