Transforming growth factor-beta signaling pathway as a therapeutic target in neurodegeneration.
Neurodegenerative diseases are becoming an increasing social and economical burden as our population ages; but current knowledge of the processes leading to these diseases is still limited, and no effective treatments are available. Neurodegeneration in Alzheimer's disease (AD) is the most common cause of dementia and afflicts an estimated 4 million people in this country alone. Because accumulation of beta-amyloid (Abeta) peptide appears central to AD pathogenesis, large efforts have been directed at understanding and interfering with Abeta production or aggregation. These efforts have largely identified the processes resulting in Abeta production from the larger amyloid precursor protein (APP) and have revealed that Abeta peptide is also produced at low levels in the healthy brain. Interestingly, Abeta production is rapidly increased after neuronal injury, and traumatic brain injury is a known risk factor for AD and Parkinson's disease. In contrast, brain injury in young individuals does not seem to result in AD, and brain injury in animal models can promote Abeta clearance. This suggests that certain factors associated with injury might be able to reduce the accumulation of Abeta. Accumulation of Abeta peptide might be reduced either directly by stimulating phagocytes or other Abeta-degrading processes, or indirectly, by reducing neuronal injury and thus lowering the production of Abeta peptide. Directing the brain's natural mechanisms for clearing Abeta or increasing neuroprotection might therefore be reasonable approaches in interfering with AD pathogenesis.
Wyss-Coray
Tony
T
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. twc@stanford.edu
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016212:Transforming Growth Factor beta