Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T.
Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease.
Glia. 2010 Feb;58(3):300-14.
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The publication from Mori et al is an important paper. It adds to the growing body of evidence that astrocytes likely play a significant role in the pathogenesis of Alzheimer disease. Overexpression of human S100β using the endogenous S100β promoter in Tg2576 mice resulted in increased total amyloid deposition, increased CAA, increased astrocytosis, and increased Iba-1 indicating a microglial reaction. The authors examine many aspects of pathology, and begin to determine the cause of increased amyloid, which appears to be increased APP processing through the β-secretase pathway. Also, the authors examine a limited number of classical inflammatory cytokines and find a modest increase in the Tg2576/S100b mice compared to the Tg2576 or S100β mice alone. What would have been interesting here would be to examine some markers of other types of inflammation, such as alternative inflammation, which has been shown to be present in the Alzheimer brain and the brains of APP transgenic mice (Colton et al., 2006).
One important point about astrocytes not addressed by the authors in this publication is that there is evidence suggesting different functional types of astrocyte. Passive astrocytes are GFAP-positive and sometimes S100β positive, have a low membrane resistance and are extensively coupled through gap junctions. Complex astrocytes are defined as GFAP-negative, S100β positive, have a high membrane resistance and are poorly coupled (Walz, 2000; Wallraff et al., 2004; Zhou et al., 2006). Selective overexpression of S100β in the current study could potentially alter the distribution of these types of astrocyte in the brain. Since these astrocytes are functionally very different, it would be interesting to assess this further in these mice.
We have previously shown that our APP/NOS2-/- mice show some evidence of a switch from passive to complex, with an apparent loss of GFAP but gain in S100b (Wilcock et al., 2008). This type of switch in astrocyte phenotype has also been observed in mild brain ischemia (Wang et al., 2008). This might be particularly relevant to the increase in CAA observed in the Tg2576/S100β mice. It is unclear from the data in the paper whether this increase in CAA is related to simply the overall increase in amyloid deposition or whether the actual ratios of parenchymal to vascular amyloid have changed. It is well known that astrocytes have an intimate relationship with the vasculature; one that is critical to brain homeostasis. Disruption of this relationship through either overall astrogliosis or altered astrocyte phenotypes due to overexpression of S100β could likely impact amyloid drainage pathways and, therefore, alter the amount of CAA.
Nevertheless, this is a very interesting and timely paper, and one that raises important questions for us all to consider in the future with respect to the role of astrocytes and inflammation in Alzheimer disease.
Wilcock DM, Vitek M, Colton CA (2008) Cerebral amyloid angiopathy results in neurovascular unit disruption in transgenic mouse models of Alzheimer’s disease. In: International Conference on Alzheimer's Disease. Chicago, IL. No abstract available.
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP.
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.
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Wallraff A, Odermatt B, Willecke K, Steinhäuser C.
Distinct types of astroglial cells in the hippocampus differ in gap junction coupling.
Glia. 2004 Oct;48(1):36-43.
Controversy surrounding the existence of discrete functional classes of astrocytes in adult gray matter.
Glia. 2000 Aug;31(2):95-103.
Wang LP, Cheung G, Kronenberg G, Gertz K, Ji S, Kempermann G, Endres M, Kettenmann H.
Mild brain ischemia induces unique physiological properties in striatal astrocytes.
Glia. 2008 Jul;56(9):925-34.
Zhou M, Schools GP, Kimelberg HK.
Development of GLAST(+) astrocytes and NG2(+) glia in rat hippocampus CA1: mature astrocytes are electrophysiologically passive.
J Neurophysiol. 2006 Jan;95(1):134-43.
This interesting publication provides more support for the hypothesis that S100B, an astrocyte-derived protein, can enhance and exacerbate the detrimental neuroinflammatory response to Aβ. Acute elevation of S100B can serve as a beneficial adaptive response of astrocytes that promotes neuronal repair by the trophic activity of S100B, but chronically elevated S100B becomes deleterious (Van Eldik and Wainwright, 2003). This study clearly demonstrates the detrimental aspects of chronic S100B overexpression. Mori and colleagues crossed a mouse that has a 4 to 6 fold overexpression of human S100B driven by the endogenous S100B promoter with the Tg2576 mouse that overproduces human Aβ1-40 and Aβ1-42. The resulting Tg2576/S100B mouse was found to have a dramatic acceleration of the Aβ-induced pathology over what is normally found in the Tg2576 mice.
At nine months of age, before abundant Aβ burden was detected in the Tg2576 mice, there were already elevated pro-inflammatory cytokines, and an increased microglia and astroglia response in the Tg2576/S100B mouse. These results suggest that low levels of Aβ and increased S100B seemed to fuel the inflammatory fire and accelerate disease progression. It is especially intriguing that the glial activation and pro-inflammatory responses occur prior to frank amyloid deposition, suggesting that S100B-induced glial inflammatory responses are active drivers of accelerated amyloid pathology rather than being passive, reactive responses to amyloid load.
These are consistent with our previous results showing that infusion of human oligomeric Aβ1-42 into the brain of the S100B-overexpressing mice led to enhanced glial activation and pro-inflammatory cytokine production, with no significant changes in amyloid plaque burden (Craft et al., 2005). Importantly, that study also showed that Aβ-infused S100B transgenic mice exhibited enhanced neuronal damage and more pronounced loss of synaptic markers compared to Aβ-infused wild-type mice, suggesting that the augmented neuroinflammatory responses lead to increasingly severe neuropathologic sequelae. These data are consistent with S100B being an important component of a pathological glia activation-neuron dysfunction cycle.
Increased levels of S100B can be found in the CSF and serum after a large number of acute brain injuries (Van Eldik and Wainwright, 2003). The results of Takashi Mori and colleagues suggest that it might be worthwhile to monitor a person’s S100B levels, as elevated S100B might increase the risk for future neuronal injury or neurodegeneration. More work on S100B is definitely warranted to determine if therapeutics targeted at reducing elevated S100B could be neuroprotective, and if S100B might be a good biomarker of neurodegenerative disease progression. The work of Takashi Mori and colleagues adds another gripping chapter to the complex story of S100B.
Craft JM, Watterson DM, Marks A, Van Eldik LJ.
Enhanced susceptibility of S-100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human beta-amyloid.
Glia. 2005 Aug 15;51(3):209-16.
Van Eldik LJ, Wainwright MS.
The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain.
Restor Neurol Neurosci. 2003;21(3-4):97-108.
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