The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APPSW mice

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

“…63 Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in rodent transgenic models that develop this disease. [64][65][66][67][68][69][70][71][72][73][74] It is therefore important to study the development of these deposits, as well as the effects they have on their cellular environment. The precise role of microglia in AD is still under intensive debate.…”

“…The idea that an immune reaction in AD is the cause of neurodegeneration comes from many reports demonstrating that amyloid plaques are often surrounded by microglial cells, [64][65][66][67][68][69][70][71][72] and the fact that cultured microglial cells react to b-amyloid by producing high levels of inflammatory cytokines, such as IL-1b, TNF-a and IL-6 among others. 75,76 As discussed earlier, this has been linked to cytokine production and neuronal death in cell cultures.…”

“…In fact, due to the in vivo data published to date, microglial cells have often been thought to be unable to penetrate the core of amyloid plaques. [70][71][72] The authors of these papers propose that b-amyloid found in senile plaques is actually produced by nearby microglial cells or that these cells have a role in the formation of b-amyloid aggregates. Their main conclusions are based on the following findings: (1) the number of microglial cells associated with senile plaques is correlated with the actual size of the bamyloid deposits, and (2) ultrastructural observations demonstrate the presence of fibrillar b-amyloid within cellular compartments of microglia.…”

“…In most postmortem studies, results indicate that microglia do not penetrate the core of the plaques and that they do not seem to eliminate the b-amyloid deposits by phagocytosis. [70][71][72] These data and the failure to demonstrate that microglial cells are able to phagocytose b-amyloid have led to the assumption that the brain's resident macrophages promote the development of the disease since they produce cytotoxic elements and are unable to clear the b-amyloid deposits.…”

Neuroprotective roles of the P2Y2 receptor

“…As described above, P2Y 2 Rs mediate the Src-dependent transactivation of the vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells that promotes upregulation of monocyte-binding proteins (e.g., VCAM-1) and a decrease in endothelial adherens junction integrity [22,89,92,101,102]. Other studies have shown that microglia are attracted to and surround Aβ plaques in both human AD brain and rodent transgenic models that develop AD-like symptoms [228][229][230][231][232][233][234][235][236][237]. Although the role of microglial cells in AD (i.e., neurotoxic vs. neuroprotective) is controversial, recent work has shown that the majority of microglia that surround amyloid plaques in an AD mouse model are derived from monocytes originating in bone marrow [233,238] and thus must pass from the bone marrow into the bloodstream through the vasculature and across the BBB to reach sites of plaque formation in the brain.…”