Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease.
Amyloid plaques appear early during Alzheimer's disease (AD), and their development is intimately linked to activated astrocytes and microglia. Astrocytes are capable of accumulating substantial amounts of neuron-derived, amyloid beta(1-42) (Abeta42)-positive material and other neuron-specific proteins as a consequence of their debris-clearing role in response to local neurodegeneration. Immunohistochemical analyses have suggested that astrocytes overburdened with these internalized materials can eventually undergo lysis, and radial dispersal of their cytoplasmic contents, including Abeta42, can lead to the deposition of a persistent residue in the form of small, GFAP-rich, astrocytic amyloid plaques, first appearing in the molecular layer of the cerebral cortex. Microglia, most of which appear to be derived from blood monocytes and recruited from local blood vessels, rapidly migrate into and congregate within neuritic and dense-core plaques, but not diffuse plaques. Instead of internalizing and removing Abeta from plaques, microglia appear to contribute to their morphological and chemical evolution by facilitating the conversion of existing soluble and oligomeric Abeta within plaques to the fibrillar form. Abeta fibrillogenesis may occur largely within tiny, tube-like invaginations in the surface plasma membrane of microglia. These results highlight the therapeutic potential of blocking the initial intracellular accumulation of Abeta42 in neurons and astrocytes and inhibiting microglia-mediated assembly of fibrillar Abeta, which is particularly resistant to degradation in Alzheimer brain.
Nagele
Robert G
RG
Department of Molecular Biology, University of Medicine and Dentistry of New Jersey/SOM, 2 Medical Center Drive, Stratford, NJ 08084, USA. nagelero@umdnj.edu
Wegiel
Jerzy
J
Venkataraman
Venkat
V
Imaki
Humi
H
Wang
Kuo-Chiang
KC
Wegiel
Jarek
J
D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D006801:Humans; D017628:Microglia / Q000473:pathology*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)