Transforming growth factor-βS in neurodegenerative disease

Abstract

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, FeSO4 (induces production of reactive oxygen species), Ca2+ ionophores, glutamate, glutamate receptor agonists and MPTP (toxic for dopaminergic neurons). TGF-β maintains mitochondrial potential and Ca2+ hemostasis 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.