Abstract
Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.
Highlights
It has been recognized that peripheral innate and adaptive immune cells play important roles in influencing brain immunity (Brioschi and Colonna, 2019)
Subsequent post hoc comparison analysis showed that phosphate-buffered saline (PBS) treated 3xTg Alzheimer’s Disease (AD) mice had a significantly worse discrimination index compared to non-transgenic animals treated with PBS (P = 0.02) or glatiramer acetate (GA) (P = 0.04) but GA treatment significantly improved behavioral performance of 3xTg mice (P = 0.01)
We found that weekly injections of GA for 4 weeks did not significantly reduce amyloid β (Aβ) pathology based on immunohistochemical staining of plaque with 6E10 and concentrations of Aβ 1–40 and 1–42 (Supplementary Figure 1), which contrasts with previous findings in more aggressive amyloidogenic models
Summary
It has been recognized that peripheral innate and adaptive immune cells play important roles in influencing brain immunity (Brioschi and Colonna, 2019). As the resident immune cells of the central nervous system, microglia actively respond to AD neuropathology. Studies have shown that patients with systemic infection and chronic inflammatory conditions are at a higher risk of developing AD (Holmes et al, 2009; Huang et al, 2015). Various systemic pro-inflammatory insults, such as peripheral LPS injections or induction of arthritis, can influence the magnitude of amyloid and tau pathology in mouse models (Lee et al, 2010; Kyrkanides et al, 2011). The mechanism of GA action in mouse models of MS is unclear, but some of the major hypotheses include polarizing helper T cells to a Th2 phenotype through bystander effect and inducing an alternatively-activated phenotype in peripheral monocytes, which in turn decreases the infiltration of proinflammatory immune cells to the central nervous system (Prod’homme and Zamvil, 2019). GA has been shown to promote neuroprotection by increasing the levels of neurotrophic factors such as BDNF (Aharoni et al, 2003), IGF-1 (Skihar et al, 2009), and IGF-2 (Zhang et al, 2010) and by increasing microglial secretion of anti-inflammatory cytokines such as IL-10 (Pul et al, 2011)
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