TRANSFORMING GROWTH FACTOR- βS IN NEURODEGENERATIVE DISEASE

Transforming growth factors- βs (TGF- βs), a family of multifunctional peptide growth factors, affect cells of the central nervous system (CNS). The three mammalian TGF- β isoforms, TGF- βs 1, 2 and 3, are expressed in adult human brain. Since neuronal degeneration is a defining feature of CNS degenerative diseases, TGF- β may be important because it can influence neuronal survival. In vitro TGF- β promotes survival of rat spinal cord motoneurons and dopaminergic neurons. In addition to direct effects on neuronal survival, TGF- β treatment of cultured astrocytes induces a reactive phenotype. Thus, TGF- β may also normalize the extracellular matrix environment in degenerative diseases. The expression of TGF- βs change in response to neuronal injury. TGF- β1 expression increases in astrocytes and microglia in animal models of cerebral ischemia, while TGF- β2 expression increases in activated astroglial cells in human neurodegenerative diseases. TGF- βs protect neurons from a variety of insults. TGF- β maintains survival of chick telencephalic neurons made hypoxic by treatment with cyanide and decreases the area of infarction when administered in animal models of cerebral ischemia. In vitro TGF- β protects neurons from damage induced by treatment with β-amyloid peptide, FeSO 4 (induces production of reactive oxygen species), Ca 2+ ionophores, glutamate, glutamate receptor agonists and MPTP (toxic for dopaminergic neurons). TGF- β maintains mitochondrial potential and Ca 2+ homeostasis and inhibits apoptosis in neurons. TGF- β does not prevent neuronal degeneration in a rat model of Parkinson's disease and has yet to be tested in newly developed transgenic mouse models of Alzheimer's disease. TGF- β is a potent neuroprotective agent which may affect the pathogenesis of neurodegenerative diseases of the CNS.