Suo Z, Wu M, Citron BA, Wong GT, Festoff BW.
Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation.
J Neurosci. 2004 Mar 31;24(13):3444-52.
PubMed.
This is an interesting study. Suo et al. propose a concept of "threshold" of Aβ in AD brain. There have been extensive studies on Aβ loads and correlation of cognitive decline. It is now clear that when so-called "subthreshold" levels of Aβ accumulate in the brain, they definitely do something, as the authors reported, i.e., sensitize microglia. More importantly, the authors claim that these subthreshold levels of Aβ may occur as oligomers. Glabe et al. (see ARF related news story) and Walsh et al. (see ARF related news story) have reported that oligomers of Aβ may be critical in causing neurodegeneration. Thus, neuron death probably has already occurred in AD brains at a very early stage, when clinical symptoms cannot yet be observed.
Finding that low doses of Aβ cannot stimulate TNFα release from mouse microglia is interesting. We previously reported that Aβ can directly stimulate release of TNFα and other cytokines from microglia derived from rapidly autopsied brains with AD (Lue et al., 2001). It suggests that properties of murine glial cells might be different from those of human, especially AD microglia, and it is important to pursue this issue further. The result of the GRK abnormality occurring prior to cognitive decline in the Tg-CRND8 animal model is interesting. It will be important to study this phenomenon in patients with AD, as it might provide an alternative therapeutic opportunity for AD treatment.
References:
Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J.
Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro.
Glia. 2001 Jul;35(1):72-9.
PubMed.
Comments
Roskamp Institute
This is an interesting study. Suo et al. propose a concept of "threshold" of Aβ in AD brain. There have been extensive studies on Aβ loads and correlation of cognitive decline. It is now clear that when so-called "subthreshold" levels of Aβ accumulate in the brain, they definitely do something, as the authors reported, i.e., sensitize microglia. More importantly, the authors claim that these subthreshold levels of Aβ may occur as oligomers. Glabe et al. (see ARF related news story) and Walsh et al. (see ARF related news story) have reported that oligomers of Aβ may be critical in causing neurodegeneration. Thus, neuron death probably has already occurred in AD brains at a very early stage, when clinical symptoms cannot yet be observed.
Finding that low doses of Aβ cannot stimulate TNFα release from mouse microglia is interesting. We previously reported that Aβ can directly stimulate release of TNFα and other cytokines from microglia derived from rapidly autopsied brains with AD (Lue et al., 2001). It suggests that properties of murine glial cells might be different from those of human, especially AD microglia, and it is important to pursue this issue further. The result of the GRK abnormality occurring prior to cognitive decline in the Tg-CRND8 animal model is interesting. It will be important to study this phenomenon in patients with AD, as it might provide an alternative therapeutic opportunity for AD treatment.
References:
Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia. 2001 Jul;35(1):72-9. PubMed.
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