Mechanisms of Mononuclear Phagocyte Recruitment in Alzheimers Disease

Abstract

Alzheimer’s disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of β-amyloid (Aβ) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Aβ levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Aβ deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Our current work does not formally determine whether degenerating Iba1-positive cells are microglia and/or infiltrating monocytes. The extent of monocyte infiltration remains controversial in the field of ALS [9,12,42,1,46], contrary to Alzheimer's disease in which monocyte infiltration has been repeatedly observed [29,30]. Our gene expression results demonstrate consistent loss of El Oussini and collaborators 15 expression of multiple genes typical of homeostatic microglia but while the monocyte marker Ly6c1 remained unaffected (Fig 6).…”

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

“…OVA-specific T cells, in contrast, fail to cluster around Ab plaques in the AD mouse model, suggesting that Ab was presented to the T cells via colocalized MHCII high APCs that were either differentiated from brain-endogenous microglia or recruited from the blood due to the increased expression of CCL2 (41,42). These observations suggest that, following the migration of T cells within the brain parenchyma, the cells either undergo apoptosis, drain from the tissue, or retain at inflammatory foci, where their cognate Ag is presented by APCs.…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Obesity-associated hypothalamic inflammation occurs in two phases, as in most inflammatory processes in the body (17,32,33). As classically defined, the first phase occurs early after exposure to the antigen and involves recruitment of inflammatory cells and local production of chemokines and cytokines; upon elimination of the threatening antigen, the second phase, or resolution phase, provides an appropriate environment to gradually return to homeostasis (17,32,33).…”

“…As classically defined, the first phase occurs early after exposure to the antigen and involves recruitment of inflammatory cells and local production of chemokines and cytokines; upon elimination of the threatening antigen, the second phase, or resolution phase, provides an appropriate environment to gradually return to homeostasis (17,32,33). When the antigenic stimulus persists, the transition from first to second phase can be disturbed leading to chronicity and eventually to functional loss (17,32,33). In the case of obesityassociated hypothalamic inflammation, the first wave of inflammatory activity is detected as early as 1 day after the introduction of large amount of dietary fats (17).…”