Prevention of Microgliosis Reduces Early Progression of Alzheimer's Disease in Mice
Microglia are innate immune cells of the brain, akin to macrophages elsewhere in the body, but with a larger portfolio of tasks, extending beyond defense against pathogens and aiding in tissue repair to include assisting in neural function and maintenance of synaptic networks. A sizable body of evidence points to increasing inflammatory activation of microglia as an important factor in the development of age-related neurodegeneration. Microglia react to signals, such as DNA debris from stressed and dying cells, or the secreted cytokines produced by senescent cells, that become more common with advancing age. When this inflammatory reaction becomes chronic, it harms the brain, diverting microglia from necessary tasks and amplifying the state of inflammation and disruption of tissue function.
Therapies that selectively destroy senescent cells, particularly senescent microglia, and therapies that clear microglia are thus of considerable interest. They have been demonstrated to reduce inflammation and the progression of brain tissue dysfunction in mice engineered to exhibit features of human neurodegenerative conditions. Today's open access paper reports on a similar but less drastic approach, in which a small molecule drug is used to reduce the inflammatory reaction of microglia to their age-damaged environment. The result is a slowing of the early progression of neurodegenerative disease, again pointing to microglial dysfunction as an important factor in the aging of the brain.
Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease
Microglia are the main tissue-resident macrophages of the brain and are important players in Alzheimer's disease (AD). There is abundant evidence for the reactivity of microglia (microgliosis) in the pathogenesis of AD. In people with AD and in AD mice there is a clear change in microglia transcriptome, showing immune activation. Reactive microglia release cytokines causing damage to healthy brain structure. Via complement-dependent pathways, reactive microglia show increased pruning of synapses leading to excessive synapse loss early in AD and ultimately cognitive impairment.
Several recent studies on AD aimed to inhibit microgliosis, and associated AD pathology, using the tetracycline derivative minocycline. Minocycline decreases the inflammatory activation of microglia, and was shown to inhibit microgliosis and alleviate defects in synaptic plasticity and cognitive behavior in mouse models of AD. Although these studies applied minocycline treatment at a relative early pathological phase, gliosis, and amyloid-β (Aβ) plaques were already apparent. The efficacy of a preventive treatment with minocycline, before the onset of gliosis and amyloid pathology has not yet been determined. This is particularly relevant because a recent clinical study on patients with mild AD, showed that minocycline treatment was not successful in slowing disease progression. This implies that a too late treatment is not successful, but leaves the possibility that inhibition of microgliosis can be effective when targeted at an early AD stage, before microgliosis becomes apparent.
The APP/PS1 mouse is a transgenic model for increased amyloidosis, resulting from the introduction of human disease-related mutations, one in amyloid precursor protein (APP) and one in presenilin 1 (PSEN1). Whereas these transgenic mouse models do not reproduce the full spectrum of pathological and clinical symptoms observed in AD, they are useful in studying early pre-pathological memory and plasticity impairments due to increased amyloidosis. Here, we determined the temporal onset of microgliosis, in relation to other AD pathological parameters, in APP/PS1 mice. Subsequently, the outcome of preventive inhibition of microgliosis on AD-related disease progression was investigated.
We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline reduced gliosis, synaptic deficits, and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Our data establish that microglial reactivity is driving early-phase AD pathology and that early treatment is effective in preventing the resulting cognitive impairments.
I wonder how these small molecule drugs compare with CSF1R inhibitor drugs that induce the body to replenish microglia: https://www.fightaging.org/archives/2022/11/clearing-microglia-reverses-age-related-disruption-of-sleeping-patterns-in-mice/
maybe a cocktail of all of the above would do the trick for reducing brain inflammation?
minocycline is a very interesting drug along with the similar doxycycline.
Min and low dose doxy have also been studied and prescribed for rosacea, acne, skin aging, periodontal disease, etc.
Mechanisms of action most often theorized is anti-inflammatory. Taken at a dose that will dampen inflammation but is too low to be antibiotic ( 20 mg for doxy up to 40 mg extended release as in the rosacea drug Oracea.
As such I'm not at all surprised that reducing brain inflammation this way can be added to the list.