Attenuation of AD‐like neuropathology by harnessing peripheral immune cells: local elevation of IL‐10 and MMP‐9

Abstract

Immunization with an altered myelin‐derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte‐derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer’s disease‐like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double‐transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (Aβ)‐plaque burden and soluble Aβ(1–42) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan). These changes were associated with a shift in the local innate immune response, manifested by increased Iba1+/CD45high macrophages that engulfed Aβ, reduced pro‐inflammatory (tumor necrosis factor‐α) and increased anti‐inflammatory (interleukin‐10) cytokines, as well as a significant increase in growth factors (IGF‐1 and TGFβ) in the brain. Furthermore, the levels of matrix metalloproteinase‐9, an enzyme shown to degrade Aβ and is associated with glial scar formation, were significantly elevated in the brain following immunization. Altogether, these results indicate that boosting systemic immune cells leads to a local immunomodulation manifested by elevated levels of anti‐inflammatory cytokines and metalloproteinases that contribute to ameliorating Alzheimer’s disease pathology.

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

“…Such cells are often considered infiltrating myeloid cells (36). Our data showed fewer such cells in the AD + ACE 10/10 mice, but these data did not reach statistical significance.…”

“…Further, we found that following immunization, increased peripheral monocyte-derived macrophages homed to Aβ plaques and facilitated their clearance (31,36). These and other studies suggest that BM-derived macrophages are more efficient than microglia in restricting Aβ plaques in mouse models of AD (29-31, 34, 36-41).…”

“…Macrophages readily absorb amyloid fibrils in vitro (59,60) and seem more efficient than microglia at restricting Aβ plaques in models of AD (30, 31, 36, 38). ADtg mice immunized with glatiramer acetate or DCs loaded with the peptide MOG45D had an increased cerebral infiltration of monocytes that resulted in substantial attenuation of AD pathology (31,36,61). These mice also had reduced cognitive impairment (62).…”

“…Following perfusion with ice-cold 0.9% saline containing 0.5 mM EDTA, harvested brains were cut in half (36). One hemisphere was used for histology, and the second hemisphere was further cut into two halves and snap-frozen for biochemical and molecular assays.…”

“…Coronal cryosections (30 μm) were treated with Target Retrieval solution (Dako) at 95°C for 30 minutes. The tissues were then permeabilized and blocked as previously described (36). The sections were stained overnight at 4°C with combinations of the following primary antibodies in PBS and blocking solution: mouse anti-human Aβ mAb clone 6E10 (1:100; Covance) recognizing amino acids 1-16 or mouse anti-human Aβ mAb clone 4G8 (1:100; Covance) recognizing amino acids 17-24; rabbit anti-CD31 polyclonal antibody (1:50; Ab28364; Abcam); rabbit anti-GFAP polyclonal antibody (1:100; G9269; Sigma-Aldrich); rabbit anti-IBA1 (1:250; 019-19741; Wako); rabbit anti-ACE polyclonal antibody (1:500) (76); and rat anti-CD45 mAb (1:25; 550539; BD Pharmingen).…”