Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of neurotoxic plaques of beta-amyloid (A?) peptides in the parenchyma of the brain. Prior to disease onset, these plaques are cleared by phagocytic myeloid immune cells in the brain, presumably resident microglia, but potentially infiltrating monocyte-derived macrophages. After disease onset, the plaques appear surrounded by these plaque-associated myeloid (PAM) cells, which are either ineffective at plaque clearance, or contribute to neuroinflammation and disease progression. While the majority of PAM cells are presumed to be microglia, it is possible that monocyte-derived macrophages may dominate the plaques and switch functionally from phagocytosis to inflammation. In healthy individuals, microglia and monocytes are quite distinct in morphology and surface marker expression, but in a diseased or activated state they are often difficult to distinguish by current methods. As a result, the precise composition of the PAM cells in AD remains unclear, hindering the understanding of the roles these cells play in neuroinflammation and the failure to clear A? plaques. Thus, there remains a need for reliable markers that are differentially expressed between microglia and monocytes in healthy and diseased brains to address this question. CD11a is differentially expressed on microglia and monocytes in healthy brains, and could potentially be used to identify whether PAM cells are microglia or monocyte in origin. CD11a expression will be examined in vivo in a variety of activation and disease conditions including LPS treatment, experimental models of monocyte infiltration, and finally in a mouse model of AD as well as in human AD patients. If successful, this tool will enable future studies to understand the molecular mechanisms that underlie the failure to clear plaques, and offer targets for therapeutic strategies to induce plaque clearance and ameliorate neurodegeneration in patients with AD.
Innate immune cells of myeloid branch are found clustered at sites of beta-amyloid plaques in patients with Alzheimer's Disease (AD), as well as it mouse models of AD. However, it remains unclear whether these plaque-associated myeloid (PAM) cells are derived from brain-resident microglia, or infiltrating monocytes from the periphery. The goal of this proposal is to validate a new marker that may distinguish microglia from monocytes to address this question, and better understand the role myeloid cells play in neuroinflammation and the failure to clear beta-amyloid plaques in AD.
| Shukla, Ankita K; McIntyre, Laura L; Marsh, Samuel E et al. (2018) CD11a expression distinguishes infiltrating myeloid cells from plaque-associated microglia in Alzheimer's disease. Glia : |
