Clearing Dysfunctional Microglia Prevents Formation of Amyloid-β Plaques in a Mouse Model of Alzheimer's Disease

Clearing Dysfunctional Microglia Prevents Formation of Amyloid-β Plaques in a Mouse Model of Alzheimer's Disease

The best Dietary supplements to Support Nitric Oxide Health

Hunting for superior recognised quality products?  Educate yourself about  these important Recognised Vitamins.

It is becoming clear that dysfunction in the supporting immune cells of the brain, the microglia, is important in the progression of neurodegenerative conditions such as Alzheimer’s disease. This certainly involves microglia becoming senescent, as demonstrated by the ability of senolytic treatments to reverse pathology in animal models of Alzheimer’s disease. But it most likely also involves a more subtle shift in the behavior of microglia, from a more regenerative M2 polarization to a more inflammatory and aggressive M1 polarization.

Both classes of microglial behavior are necessary in the grand scheme of things, but aging appears to be accompanied by an excess of M1 and too few M2 microglia (and macrophages as well, which have a similar set of behaviors) in most circumstances and tissues examined to date. The causes of this shift in cell behavior are barely explored at this point; it is unclear how it relates to the underlying molecular damage that drives aging. Nonetheless, it is certainly harmful.

Alzheimer’s disease (AD) is a progressive, age-related neurodegenerative disorder thought to be triggered by the appearance and build-up of amyloid-β (Aβ) plaques in the cortex. Genome-wide association studies have identified numerous genes that confer increased risk for developing the disease; however, the mechanisms underlying plaque formation remain unclear. Within the central nervous system (CNS), microglia perform homeostatic maintenance, immune-related, and phagocytic functions. Their reported capacity for Aβ phagocytosis and clearance led to the suggestion that age-related changes in microglial function reduce clearance of neuronally derived Aβ from the brain, thus allowing plaque formation.

We and other groups report that following the initial period of plaque formation, microglia surround the plaques and subsequently mount a harmful and non-resolving inflammatory response. Despite this response, however, Aβ clearance and plaque modulation/dynamics is unaffected, yet the removal of the microglia at advanced stages of pathology protects against synaptic and neuronal loss.

Here, we set out to explore the contributions of microglia to plaque formation in the initial stages of the disease, which requires prolonged depletion of microglia throughout the plaque-forming period. To that end, we designed, synthesized, and optimized a potent, specific, orally bioavailable, and brain-penetrant CSF1R inhibitor, PLX5622, to deplete microglia for more than 6 months in 5xFAD mice. With the elimination of microglia, we uncovered critical roles of these cells in plaque formation, compaction, and growth, mitigating neuritic dystrophy, and modulating hippocampal neuronal gene expression in response to Aβ pathology.

Ultimately, these data demonstrate that microglial elimination is associated with the prevention of plaque formation and the downregulation of hippocampal neuronal genes that occur in a preclinical model of AD progression. These results indicate that microglia appear to contribute to multiple facets of AD etiology – microglia appear crucial to the initial appearance and structure of plaques, and following plaque formation, promote a chronic inflammatory state modulating neuronal gene expression changes in response to Aβ/AD pathology.


Read additional info on N . O . and Heart health and wellness.

Comments are closed.