A report in last week's Cell suggests that TGF-β1, one of the three mammalian isoforms of that growth factor, can protect against excitotoxic neurodegeneration, which is thought to be related to the pathogenesis of several diseases including Alzheimer's disease (AD). Tony Wyss-Coray and colleagues at Stanford University, the University of California at San Diego, and the VA Palo Alto Health Care System, California, came to this conclusion after studying transgenic TGF-β1 mice.

First author Thomas Brionne and colleagues tested the protective effect of the cytokine by increasing its expression in astrocytes. In normal mice, the authors found that kainic acid-induced excitotoxic injury is manifested in the neocortex by about 25 and 60 percent loss of MAP-2 and calbindin activity, respectively. However, quadrupling TGF-β1 completely reversed these losses. In a similar test for its effect on chronic neuronal injury, Brionne found that the same increase in the growth factor could protect against the age-dependent loss of MAP-2 and synaptophysin that occurs in ApoE-negative mice.

Having found that overexpressing TGF-β1 in astrocytes can protect in these neurodegeneration models, the authors then asked what effect deficiency of the protein may have. To test this, they made TGF-β1-negative mice. Heterozygotes had a 17-fold increase in apoptotic cells in coronal brain sections when treated with kainic acid, while homozygotes showed gross developmental deficiencies (for example, a 30 percent loss in body weight by five weeks of age) and over five times as many TUNEL-positive cells as normal littermates, indicating significantly more cellular degeneration. The authors also found that primary neurons cultivated from TGF-β1-negative mice were extremely short-lived—only about one-third as many cells as wild-type survived after five days.

These results indicate that the TGF-β1 pathway may be critical for protection from certain forms of neuronal damage. The authors also point out that "genetic polymorphisms in the human TFG-β1 gene are associated with different levels of TGF-β1 in the serum," suggesting that such differences may contribute to susceptibility to neurodegenerative diseases. In support of this, Wyss-Coray and colleagues have previously reported that the growth factor promotes clearance of Aβ by microglia and protects mice from Aβ deposition (see Wyss-Coray et al., 2001), and that AD correlates with lower levels of the protein in the cortex. However, it is worth noting that overexpression of TGF-β1 was also shown to lead to and increase expression of APP (see ARF related news story). And earlier work by Wyss-Coray had suggested that TGF-β1 may indeed promote amyloid deposition (Wyss-Coray et al., 1997), and that chronic overproduction of TGF-β1 in astrocytes promotes AD-like degeneration of small blood vessels in the brain (Wyss-Coray et al., 2002), so ironing out the potential benefits and harm of this ubiquitous growth factor may need further study.—Tom Fagan


  1. Regarding the paradoxical actions of TGFβ in brain, where the factor appears to be either protective against neuronal degeneration, as reported in this study, or deleterious, promoting inflammation, hydrocephalus, and vascular fibrosis and amyloidosis, (Wyss-Coray et al., 1995; 1997; 2000a), the following aspects should be taken into consideration:

    1. The importance of the amount of TGFβ released. At physiological amounts the factor may be anti-inflammatory and neurotrophic, while when released in excess or in the absence of counter-regulatory elements, TGFbeta may turn to be proinflammatory and cause severe vascular abnormalities. There are other instances where the chronic dysregulated production of angiogenic factors, e.g., VEFG, have deleterious consequences (Detmar et al., 1998).

    2. Although the studies describing protective and detrimental effects of TGFβ have been performed on apparently the same lines of TGFβ overexpressing mice, different animal batches were used. The present study by Brionne et al. does not disclose if, in the same animals where TGFβ protected against kainic-acid induced degeneration, there were signs of vascular alteration (e.g., fibrosis and deposition of thioflavin-positive material) or glia activation, that were reported in the same lines previously (Wyss-Coray and col., 1995, 1997, 2000a). Whether the deleterious actions on vessels coexist with the protective actions on neurons is an intriguing question. If they don’t, a comparison between brain TGFβ contents in the animals used in the different studies would have helped to clarify if the opposite actions of TGFβ correlate with different degrees of production of the cytokine.

    3. Studies in our lab using TGFβ-overexpressing mice have confirmed the pathological actions of the cytokine, including severe astrocytosis and microglia activation, hydrocephalus, tissue damage and robust deposition of thioflavin-positive material in vessels and meninges as reported by Wyss-Coray et al., 2000b. However, in contradiction with previous reports (Wyss-Coray et al., 1997; Lesne et al., 2003), we have found no evidence that there is upregulation of APP in these animals, nor that the thioflavin-labeled deposit contains amyloid-β, or any other amyloid for that matter (Galea et al., 2002). The notion that TGFβ-induced inflammation can cause Alzheimer disease-like vascular amyloid angiopathy should be thus thoroughly revised.

    4. In conclusion, work in mice demonstrates the potential of TGFβ to perform “good” and “bad” actions in brain. The questions remains as to: i) what exactly determines that TGFβ be neuroprotective or detrimental; ii) the mechanisms underlying both actions; iii) the amyloidogenic role of TGFβ in vivo; and iv) whether the TGFβ overexpression detected in human brains in Alzheimer disease (Wyss-Coray et al., 1997) contributes to the pathology, or is a protective reaction. The evidence in this regard is at the moment just correlative.

  2. Q&A with Tony Wyss-Coray. Questions by Tom Fagan.

    Q: In your recent paper, you show that TGF-β1 may offer protection against excitotoxic injury to neurons. In previous papers, you had seen evidence that the cytokine may be toxic. Do the present observations take precedence?
    A: We reported previously that TGF-β1 has detrimental effects on the cerebrovasculature in old TGF-β1 transgenic mice. This was not due to a toxic effect but more likely due to an inhibition of regenerative activities in blood vessels. From studies in peripheral organs and cell culture, it is evident that TGF-βs are produced by, and modulate, almost any cell type in the body. It is increasingly clear that TGF-βs can often exert positive and negative effects on a given biological process based on TGF-β concentration and receptor composition. For example, low levels of TGF-β1 appear to promote angiogenesis and vascular cell proliferation, but high levels inhibit cell growth and promote differentiation.

    Consistent with these effects in the periphery, overexpression of TGF-β1 from astrocytes at intermediate to high levels resulted in vascular fibrosis and amyloidosis (defined as thioflavin S-positive deposits) in our model. In aged mice, the vascular changes were more prominent and accompanied by vascular cell abnormalities. Overexpression at very high levels resulted in hydrocephalus, likely due to excessive production of extracellular matrix proteins at the sites of CSF resorption. We have not investigated the effects of low levels or acute production of TGF-β1 in the CNS.

    Our latest experiments show that TGF-β1 has trophic effects on neurons that cannot be substituted by other factors. These effects are likely to be independent of the vasculature, since survival of isolated TGF-β1-deficient neurons is impaired. It will be important to dissect the molecular mechanisms underlying this dependence and determine whether these effects are direct or involve glial cells.

    Finally, we observed and reported prominent effects of TGF-β1 on glial cells in TGF-β1 transgenic and knockout mice. TGF-β1 overexpression results in a prominent astrocytosis, particularly around cerebral blood vessels, and we have speculated that this activation is a response to TGF-β1’s effects on endothelial cells (these cells express unique TGF-β receptors, called endoglin and ALK1, which are most likely not expressed on other CNS cells). TGF-β1 overexpression resulted also in increased microglial activation in the hippocampus of aged mice but, curiously, lack of TGF-β1 expression resulted in an even more dramatic activation of these cells (but not in astrocytosis).

    Taken together, TGF-β1 appears to modulate activation states and behavior of all cell types we have analyzed. Obviously, we are just at the beginning of trying to understand what the consequences of TGF-β1’s actions are on these cells.

    Q: Has your view of the role of TGF-1 changed over the past six years?
    A: Not in the sense that we found contradictory effects, but that I did not anticipate its importance. The work with TGF-β1 transgenic mice has been interesting and rewarding. I had never expected that we would see—and keep seeing—so many different effects of this factor in the brain.

    Q: In your recent paper you expressed TGF-β1 in astrocytes. Is it expressed in neurons, too? Is its neuronal expression physiologically relevant?
    A: TGF-β1 appears to be expressed by neurons, but data are sketchy. Clearly, neuroblastoma cells express TGF-β1. More importantly, however, neurons express functional TGF-β receptors, and primary hippocampal neurons can be stimulated by TGF-β1. It is too early to say at this moment what the physiological role of TGF-β signaling in neurons is. Our experiments, together with studies by many others, show that it might have a protective function in neurons; others have suggested that it modulates synaptic facilitation, or promotes neuronal cell death during embryogenesis. Again, these functions are not exclusive.

    Q: In her comment, Elena Galea mentioned some factors, such as the level of expression, the type of animals used, etc., that may explain the apparent differences in response to TGF-β. How do you explain these differences?
    A: I agree with most comments made by Dr. Galea, but I am not sure how she arrives at the conclusion: “The notion that TGF-β1-induced inflammation can cause Alzheimer’s disease-like vascular amyloid angiopathy should be thus thoroughly revised.” Our studies provide clear evidence that TGF-β1 overexpression from astrocytes in our model results in cerebrovascular amyloidosis (thioflavin S-positive deposits) (Wyss-Coray et al., 1997) and degeneration in old age ( Wyss-Coray et al., 2000). When these mice were crossed with hAPP mice, we observed a dramatic change in distribution of human Aβ: Most Aβ accumulated in cerebral blood vessels in hAPP/TGF-β1 mice (Wyss-Coray et al., 1997). Interestingly, there was a three- to fourfold reduction in Aβ in the brains of these mice. We concluded that TGF-β1 promotes amyloidogenesis in the vasculature while reducing Aβ deposition overall (Wyss-Coray et al., 2001). We were also able to show that, in human AD cases, TGF-β1 mRNA levels correlated positively with amyloid deposition in blood vessels and that TGF-β1 immunoreactivity was increased in blood vessels with amyloid deposits. Moreover, amyloid deposition in the vasculature correlated inversely with deposition in parenchymal plaques, a finding supported by several other groups, most recently by Tian et al., 2003.

    At this point, we still don’t know what the nature of the thioflavin S-positive deposits is in TGF-β1 single transgenic mice. Like many other pathologists, we called the deposits amyloid because of their specific color-imparting properties in binding thioflavin S. We believe that a biochemical analysis of the deposits will be necessary to identify their main protein component, but this experiment is very challenging to do, given the small quantities that can be obtained from a mouse brain (this is what we concluded in our initial report in Nature, 1997). Several groups have shown that TGF-β1 induces APP expression in cell culture, but we were not able to confirm this in vivo and never said so (this was misquoted by Dr. Galea). Unpublished observations from our lab showed a shift from shorter to KPI-containing splice forms of mouse APP at the mRNA level in TGF-β1 transgenic mice, but overall, there was no increase in mouse APP mRNA. Whatever the deposits are, they bind thioflavin S, are electron dense, and most importantly, they colocalize with human Aβ in hAPP/TGF-β1 mice. We demonstrated that TGF-β1 overproduction results in excessive accumulation of basement membrane protein in the vascular wall. We hypothesize that this results in the trapping of Aβ while it is being cleared, at least in part, via interstitial drainage channels along blood vessels or is transported across the blood-brain barrier into the plasma. There are likely small amounts of mouse Aβ present in these deposits, but this is a moot point given the prominent effect of TGF-β1 on human Aβ deposition.

    Q: Do you think the elevated levels of TGF-β in AD brains are a cause or an effect of AD?
    A: I don’t think increased TGF-β1 expression underlies AD. Rather, any form of cellular injury, as well as aging, results in increased production of TGF-β1 and activation of TGF-β signaling. There is a good possibility that this TGF-β1 modulates AD pathogenesis, similar to what we can observe in our mouse models.

    Q: What needs to be done next to nail down the role of TGF-β?
    A: Most studies on TGF-β focus on its peripheral effects. We need much more research focusing on its physiological function in the CNS. We recently generated a mouse that harbors a TGF-β response element in all cells of the body. The brain, in particular the hippocampus, showed several-fold higher baseline activity for this TGF-β response element than all other major organs (see ARF related news story). This further underlines the potential importance of this signaling pathway in the CNS. We will need to generate mouse models that directly inhibit or stimulate TGF-β signaling in a given cell type in vivo (using dominant negative or active TGF-β receptor transgenes or conditional knockouts), or use viral constructs to achieve this. Such models will be needed to further dissect the pathophysiological role of TGF-β in neurodegeneration and other CNS diseases, but they will also be helpful for electrophysiological and behavioral studies. Cell culture experiments using primary CNS cells will be needed to study the molecular mechanisms of TGF-β signaling. Again, we are just at the beginning.


    . Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997 Oct 9;389(6651):603-6. PubMed.

    . Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am J Pathol. 2000 Jan;156(1):139-50. PubMed.

    . TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001 May;7(5):612-8. PubMed.

    . Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease. Neurosci Lett. 2003 Dec 4;352(2):137-40. PubMed.

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News Citations

  1. Astrocytes—Part of the Solution or Part of the Problem?

Paper Citations

  1. . TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001 May;7(5):612-8. PubMed.
  2. . Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997 Oct 9;389(6651):603-6. PubMed.
  3. . Molecular and functional dissection of TGF-beta1-induced cerebrovascular abnormalities in transgenic mice. Ann N Y Acad Sci. 2002 Nov;977:87-95. PubMed.

Further Reading


  1. . Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002 Aug 1;35(3):419-32. PubMed.

Primary Papers

  1. . Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron. 2003 Dec 18;40(6):1133-45. PubMed.