Development of beta-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies.
Alzheimer's disease (AD) is a form of dementia in which people develop rapid neurodegeneration, complete loss of cognitive abilities, and are likely to die prematurely. At present, no treatment for AD is known. One of the hallmarks in the development of AD is the aggregation of amyloid protein fragments in the brain, and much evidence points towards beta-amyloid fragments being one of the main causes of the neurodegenerative processes. This review summarises the present concepts and theories on how AD develops, and lists the evidence that supports them. A cascade of biochemical events is initiated that ultimately leads to neuronal death involving an imbalance of intracellular calcium homeostasis via activation of calcium channels, intracellular calcium stores, and subsequent production of free radicals by calcium-sensitive enzymes. Secondary processes include inflammatory responses that produce more free radicals and the induction of apoptosis. Recently, several new strategies have been proposed to try to ameliorate the neurodegenerative developments associated with AD. These include the activation of neuronal growth factor receptors and insulin-like receptors, both of which have neuroprotective properties. Furthermore, the role of cholesterol and potential protective properties of cholesterol-lowering drugs are under intense investigation. Other promising strategies include the inhibition of beta- and gamma-secretases which produce beta-amyloid, activation of proteases that degrade beta-amyloid, glutamate receptor selective drugs, antioxidants, and metal chelating agents, all of which prevent formation of plaques. Novel drugs that act at different levels of the neurodegenerative processes show great promise to reduce neurodegeneration. They could help to prolong the time of unimpaired cognitive abilities of people who develop AD, allowing them to lead an independent life.
Hölscher
Christian
C
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland. c.holscher@ulster.ac.uk
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020013:Calcium Signaling / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology* / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents