Microglial replacement reverses brain aging in mice
Microglia (green) growing in tissue culture alongside neurons, whose processes are shown in red. Activated microglia have irregular morphologies; resting cells appear round. Credit: Gerry Shaw via Wikimedia Foundation

Microglia (green) growing in tissue culture alongside neurons, whose processes are shown in red. Activated microglia have irregular morphologies; resting cells appear round. Credit: Gerry Shaw via Wikimedia Foundation

The immune system is generally considered a good thing, and for the most part it is. However, new findings suggest that we may be able to rejuvenate the aging brain by crippling (albeit temporarily) a major component of its immune system.

The cells in question are microglia, the resident immune cells of the central nervous system, which prowl around our brain and spinal cord looking for signs of infection or injury. In that sense, they are analogous to macrophages, although the two kinds of cells are developmentally and anatomically quite distinct. While macrophages serve as workhorses of immunity in the rest of the body, microglia are the linchpin of a separate, devoted immune system that operates behind the blood–brain barrier. In addition to their immune functions, microglia also play key roles in tissue homeostasis and synaptic connectivity.

Over the course of aging, microglia become functionally impaired—less able to move through the tissue and survey for alarm signals, yet more prone to launch intense and often inappropriate inflammatory responses. These senescent microglia contribute to age-related decline in cognitive function, and as we reported here recently, may drive neurodegenerative disease.

Thus, if we could non-invasively eliminate senescent microglia and replace them with functionally “young” cells, we might be able to slow—or even roll back—the deleterious effects of aging on the brain. A recent study did just that.

The study

In a collaboration led by Kim Green of UC–Irvine, the researchers got rid of microglia by inhibiting the colony-stimulating factor 1 receptor (CSF1R), which the cells absolutely require for life. For this purpose, they took advantage orally bioavailable CSF1R inhibitors, created by the Berkeley-based drug developer Plexxikon, that can completely eliminate microglia from the brain within just a few days. Removal of the drug allows the microglia to regrow, a process that takes a couple of weeks.

The microglia that grew back lacked markers of senescence, and from the standpoint of morphology, gene expression, and behavior, they resembled the microglia of younger mice.

The functional consequences in the brain were dramatic: Aged mice exhibited improvements in cognition and recovered from deficits in long-term potentiation, a key aspect of learning and memory. At the tissue level, the researchers noted an increase in the number of dendritic spines, where neurons receive input from upstream nerve cells—a rough index of functional connectivity.

Moreover, the entire process occurred without any derangement of the normal immunological or inflammatory characteristics of the brain.

The ramifications

I find two features of this story highly compelling. First, microglial replacement is not merely slowing, or even halting, age-related damage, but actually reversing it. In addition to the obvious clinical significance, this teaches us something about the biology of the aging brain: If replacing senescent microglia with fresh cells can restore brain function, it implies that (at least in non-pathological circumstances) much of the fundamental circuitry of the brain must remain intact even after functional decline has set in.

Second, this is an acute solution to a chronic problem: the mice only needed to be treated with CSF1R inhibitors for a few days, after which natural tissue homeostasis mechanisms repopulated the brain with ‘young’ microglia. Because this potentially powerful preventive strategy does not require indefinite, regular administration of a drug, it would be very attractive from the standpoint of a potential human patient.

Of course, to take advantage of this approach, the CSF1R inhibitors need to be approved for clinical use in humans. What would be the ideal path to market? It is most straightforward to imagine that the drugs could be pitched as preventive medicine for neurodegeneration — but as we know, the FDA sets a very high bar for trials of treatments for Alzheimer’s and other forms of dementia. (That said, regulatory have shown signs of relaxing these requirements, opening the door to drugs that treat very early-stage disease or even act preventively).

Alternatively, one could imagine CSF1R inhibitors being used to modulate microglial activity in cases of traumatic brain injury (TBI), in which microglia play key roles in inflammation. Even more fancifully, the emerging relationship between microglial activation and schizophrenia might create further opportunities for an approvable indication.

Once approved, these drugs could be used in conjunction with senolytics to target senescent microglia, rolling back age-related cognitive decline and even helping to prevent neurodegeneration.

Elmore et al. “Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice.” Aging Cell 2018 • DOI