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
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