Linh Le - PhD Candidate, Neuroscience Graduate Program
Alzheimer’s disease (AD) is the most common cause of age-related dementia, characterized by well-known pathological hallmarks including extracellular amyloid β (Aβ) plaque deposition and neurofibrillary tangle accumulation. In the past decade, neuroinflammation has emerged as a crucial contributor to disease pathogenesis thanks to GWAS studies revealing various genetic variants of immune receptors as AD risk factors. These receptors are largely expressed by microglia, the resident innate immune cells of the central nervous system (CNS), making them a promising translational target for disease-modifying therapies. Here, we sought to elucidate the effects of two different approaches to modulating microglia functions in AD-like mouse models.
First, building on a multitude of evidence on the anti-inflammatory effects of the neurotransmitter norepinephrine (NE) and our previous work revealing that NE inhibits microglia surveillance activity via the β2 adrenergic receptor (AR), we explored the contribution of microglial β2 adrenergic signaling to AD pathology in 5xFAD mice, a commonly used model of amyloidosis. We observed an early degeneration of NE projections followed by locus coeruleus (LC) neuronal loss in more advanced disease stages, accompanied by a mild decrease in the levels of NE and its metabolite normetanephrine. Interestingly, we found that microglia in 5xFAD mice lost their sensitivity to β2AR signaling early and this was particularly evident in microglia that were in close proximity to Aβ plaques. We also described the important role of microglial β2AR signaling on AD, revealing opposing effects on amyloid pathology, whereby activation of microglial β2AR attenuated plaque deposition whereas inhibition worsened plaque pathology.
We next asked whether global pharmacologically-induced renewal of microglia, which is suggested to have “rejuvenating” and beneficial effects, could be a potential pathology-modifying therapy for AD. We induced microglial repopulation by depleting microglia with PLX5622 (a colony stimulating factor 1 receptor (CSF1R) inhibitor) and allowing them to replenish upon PLX5622withdrawal in two common models of AD: APP/PS1 and 3xTg mice. However, we observed no changes in amyloid pathology after forced repopulation of microglia, accompanied by a lack of cognitive improvement in a battery of behavioral tests.
We then set out to address sexual dimorphism in microglia, which potentially underlies the well-known differences in amyloid pathology in male versus female mice, with pathogenesis in females progressing much faster. To first understand how male and female microglia might differ in their survival and proliferation mechanisms, we examined the sex-specific effects of CSF1R inhibition using PLX3397. We confirmed that CSF1R inhibition resulted in significantly less depletion in female mice compared to male mice. Transcriptomic analysis of microglia revealed differential upregulation of autophagy, mitochondrial dynamics, and surveillance in PLX3397-treated female microglia compared to male microglia. Further studies are warranted to establish mechanistic links between these observations.
Taken together, our results suggested that specific, rather than global, manipulation of microglia might be effective in treating AD. Specifically, we highlighted the potential of leveraging microglial β2AR signaling for disease-modifying therapy.
Dec 11, 2023 @ 12:00 p.m.Hybrid Event
Medical Center | Ryan Case Method Rm (1-9576)
Host: Ania Majewska, PhD & Kerry O’Banion, MD, PhD - Advisors