Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer’s Disease

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.

Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology

“…4 ). These findings highlight the value of assessing Tau pathology through multiple approaches [ 55 ] and suggest a potential disease-modifying benefit of our repopulation paradigm.…”

Glatiramer Acetate Immunomodulation: Evidence of Neuroprotection and Cognitive Preservation

“…These studies found an increase in the Th2-derived regulatory anti-inflammatory cytokines Interleukin-4 (IL-4) and Interleukin-10 (IL-10), primarily around Aβ plaques, and a reduction in proinflammatory mediators (i.e., TNFα, IL-6) [31,104,105,125]. In fact, several studies found that there is an important role for GAdriven immunomodulation, affecting both the central and peripheral immune responses, leading to regulation and repair causing Aβ removal in AD models [31,32,95,124,126,127]. One study found that GA-activated central immune cells, such as microglia, degraded, engulfed, and cleared soluble fibrillar Aβ plaques [125].…”

“…The new phenotypes were associated with proliferation and survival of oligodendrocytes, preserved synaptic processes and increased levels of neural progenitor cells, showing signs of enhanced neurogenesis and neuroprotection [95,127]. [126] All studies utilized transgenic models of AD. Animals in the treatment groups received 100 µg/s.c./qw, unless otherwise specified; AD: Alzheimer's disease; Aβ: Aβ; MWMT: Morris water maze test; RAWM: radical arm water maze; SGZ: subgranular zone; m: male; qm: monthly; BMT: Barnes maze test; MΦ BM : bone-marrow-derived monocytes/macrophages; DG: dentate gyrus; MEA: multi-electrode analysis; f/oAβ 42 : fibrillar/oligomeric Aβ 42 ; IOP: intraocular pressure; RT-PCR: real time-polymerase chain reaction; WB: Western blot; EGR1: early growth response gene 1; MMP9: matrix metallopeptidase 9; FAD-familial Alzheimer's disease; DT-diphtheria toxin.…”

“…AD animal models underwent thorough CNS analyses for AD-like pathology such as Aβ plaques. Neural tissue taken from the GA-treated ADtg mice displayed enzymatic degradation of Aβ plaques as well as reduction in and regulation of central inflammation [31,95,[126][127][128]. All the observed ADtg had decreased Aβ 42 levels, likely due to a GA-stimulated increase in macrophage-aided removal of the Aβ plaques [31,104,105,124,125,127,128].…”

“…All the observed ADtg had decreased Aβ 42 levels, likely due to a GA-stimulated increase in macrophage-aided removal of the Aβ plaques [31,104,105,124,125,127,128]. Specifically, GA was shown to reduce Aβ depositions in the cerebral vasculature, retina, and parenchyma [18,104,105] and was linked to amelioration of AD signs, both in the cerebrum, the retina, hippocampus, brain cortex, and other parenchymal areas [105,124,126,129]. Additionally, levels of MMP9 protein, an enzyme known to degrade Aβ, were increased [31,32].…”