Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases

Abstract

Inflammation-mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with antiinflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque-developing mice with amyloid beta peptide (Abeta) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neurodegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets.

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

“…It would thus seem that blood-derived microglia are beneficial to the diseased CNS. Although it has previously been suggested that microglial cells are unable to phagocytose b-amyloid in vivo, 76 our data demonstrate that newly differentiated microglial cells originating from the blood are able to remove bamyloid from extracellular environment, whereas resident microglia are ineffective at b-amyloid phagocytosis. 98 These data and the fact that b-amyloid is often found within lysosomes of bone marrowderived microglia suggest that newly infiltrated microglial cells may indeed be able to clear b-amyloid deposits by phagocytosis.…”

“…Human brain samples of patients diagnosed with AD are usually obtained from very old subjects, a time where the disease is in its final stages. Our study may thus explain reports of human studies demonstrating a lack of b-amyloid phagocytosis by microglial cells, 76 since we have shown that b-amyloid is mostly phagocytosed by microglia originating from the blood and less often by resident microglial cells and that plaques in the later stages of their development contain many resident microglia, whereas there are fewer of their blood-derived counterparts. It is possible that resident microglia take part in b-amyloid deposition, [70][71][72] while bone marrow-derived cells serve to eliminate these deposits.…”

“…75,76 As discussed earlier, this has been linked to cytokine production and neuronal death in cell cultures. [76][77][78][79][80] There are multiple b-amyloid isoforms present in the CNS, though it seems that neurotoxic properties observed in vitro are mostly attributed to the bAmyloid 1-42 isoform.…”

“…75,76 As discussed earlier, this has been linked to cytokine production and neuronal death in cell cultures. [76][77][78][79][80] There are multiple b-amyloid isoforms present in the CNS, though it seems that neurotoxic properties observed in vitro are mostly attributed to the bAmyloid 1-42 isoform. 78,80 Some indicate that microglial activation is induced by aggregated b-amyloid, 81 whereas others report that diffuse forms may also be responsible for the immune response seen in this disease.…”

Microglial responses to dopamine in a cell culture model of Parkinson's disease

“…Human elderly microglia were isolated and maintained in culture as previously described (Lue et al, 1996(Lue et al, , 2001Walker et al, 2005), using methods similar to those originally developed by Kim (1985). The cultured microglia expressed antigenic, morphologic, and other criteria of microglia, and were approximately 98% pure, confirming previous studies (Lue et al, 1996(Lue et al, , 2001Walker et al, 2005).…”