CELLULAR SIGNALING ROLES OF TGF-BETA, TNF-ALPHA AND BETA-APP IN BRAININJURY RESPONSES AND ALZHEIMERS-DISEASE

beta-Amyloid precursor protein (beta APP), transforming growth factor beta (TGF beta), and tumor necrosis factor-alpha. (TNF alpha) are rema rkably pleiotropic neural cytokines/neurotrophic factors that orchestr ate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their assoc iation with cytopathological alterations in Alzheimer's disease. Astro cytes and microglia each produce and respond to TGF beta and TNF alpha in characteristic ways when the brain is injured. TGF beta, TNF alpha and secreted forms of beta APP (sAPP) can protect neurons against exc itotoxic, metabolic and oxidative insults and may thereby serve neurop rotective roles. On the other hand, under certain conditions TNF alpha and the fibrillogenic amyloid beta-peptide (A beta) derivative of bet a APP can promote damage of neuronal and glial cells, and may play rol es in neurodegenerative disorders. Studies of genetically manipulated mice in which TGF beta, TNF alpha or beta APP ligand or receptor level s are altered suggest important roles for each factor in cellular resp onses to brain injury and indicate that mediators of neural injury res ponses also have the potential to enhance amyloidogenesis and/or to in terfere with neuroregeneration if expressed at abnormal levels or modi fied by strategic point mutations. Recent studies have elucidated sign al transduction pathways of TGF beta (serine/threonine kinase cascades ), TNF alpha (p55 receptor linked to a sphingomyelin-ceramide-NF kappa B pathway), and secreted forms of beta APP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge o f these signaling pathways is revealing novel molecular targets on whi ch to focus neuroprotective therapeutic strategies in disorders rangin g from stroke to Alzheimer's disease.