Therapeutic effects of glatiramer acetate and grafted CD115⁺monocytes in a mouse model of Alzheimer’s disease

Abstract

Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-β plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-β protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-β; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-β plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-β, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-β1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-β phagocytosis, and the amyloid-β-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-β as well as regulation of brain inflammation.

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

“…Curcumin is a natural and safe fluorochrome that crosses the blood-brain and -retinal barriers and binds to Aβ fibrils and oligomers with high affinity [490, 527, 538–551], with the ability for ex vivo and in vivo visualization when specifically bound to retinal Aβ plaques (Figure 7A–B) [485, 490, 527]. This approach enabled non-invasive detection and monitoring of desecrate retinal Aβ deposits in live animal models of AD [490], including the capability to track the dynamic appearance and clearance of individual plaques and their substantial reduction after glatiramer acetate (GA) immunotherapy [527, 552, 553]. …”

β-amyloid, microglia, and the inflammasome in Alzheimer’s disease

“…This was later confirmed by Naert and colleagues [59]. More recent reports showed that cells expressing monocyte markers are associated with plaques in two transgenic models of Aβ deposition [60], and that adoptively transferred monocytes home in to these plaques [61]. Furthermore, while CD36 is expressed in microglial cells, its level of expression on peripheral monocytes and macrophages is more than 100-fold higher than in microglial cells [16].…”

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

“…Among the family of matrix metalloproteinases (MMP), MMP-9 and MMP-8 are important for the migration of microglia during embryogenesis [3]. Expressed MHC class II [41] Highly expressed MHC class II [21] Expressed MHC class II [42] Neurotoxicity Produced pro-inflammatory cytokines [43] Produced pro-inflammatory cytokines [44] Produced pro-inflammatory cytokines (in brain) [45] Increased ROS [16,46] Reduced ROS [16] Reduced ROS (in brain) [47] Produced nitric oxide [48] Expressed the inducible form of nitric oxide synthase (in brain) [49] Produced nitric oxide [42] Phagocytosis Dead photoreceptors and cell debris (dead cells in brain) [50,51] Unclear Dead photoreceptors and cell debris [50] Living stressed photoreceptors (living neurons in brain) [52,53] Unclear Unclear Amyloid deposits clearance Impaired Aβ clearance and facilitated Aβ deposition [16] Increased Aβ clearance [14,16] Increased Aβ clearance [54] Neuroprotection Produced neurotrophic factors [55] Unclear Produced neurotrophic factors [15] Unclear Unclear Produced anti-inflammatory cytokines [56] Vascularization Promoted the formation of CNV (VEGF, PDGFβ, and ICAM) [55] Pathological neovascularization (IL-1β) [44,57] Promoted the formation of CNV [58] Unclear Physiological neovascularization [59] Unclear…”