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Review Drosophila models of Alzheimer's amyloidosis: the challenge of dissecting the complex mechanisms of toxicity of amyloid-beta 42. 2008
Iijima K, Iijima-Ando K. · Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA. · J Alzheimers Dis. · Pubmed #19096154 No free full text.
Abstract: Alzheimer's disease (AD) is the most common form of senile dementia, and a cure is desperately needed. The amyloid-beta42 (Abeta42) has been suggested to play a central role in the pathogenesis of AD. However, the mechanism by which Abeta42 causes AD remains unclear. To understand the pathogenesis and to develop therapeutic avenues, it is crucial to generate animal models of AD in genetically tractable organisms. Drosophila is a well-established model system for which abundant genetic tools are available. Moreover, its well organized brain permits the study of complex behaviors such as learning and memory. We have established transgenic flies that express human Abeta42 in the nervous system. These flies developed age-dependent short-term memory impairment and neurodegeneration. In this review, we will first describe transgenic Abeta42 fly models and discuss the unique features of this system compared to mouse AD models. Secondly, we will discuss the usage of the fly models to evaluate currently proposed therapeutic strategies. Thirdly, we will briefly review the results of a genetic screen for modifiers of Abeta42 toxicity in the fly model. Finally, we will discuss how to dissect the complex mechanisms of Abeta42 toxicity focusing on its aggregation propensity using the fly model system.
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Article Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. free! 2008
Iijima-Ando K, Hearn SA, Granger L, Shenton C, Gatt A, Chiang HC, Hakker I, Zhong Y, Iijima K. · Laboratory of Neurogenetics and Pathobiology, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. · J Biol Chem. · Pubmed #18463098 links to free full text
Abstract: The amyloid-beta42 (Abeta42) peptide has been suggested to play a causative role in Alzheimer disease (AD). Neprilysin (NEP) is one of the rate-limiting Abeta-degrading enzymes, and its enhancement ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of Abeta amyloidosis. In addition to the extracellular Abeta, intraneuronal Abeta42 may contribute to AD pathogenesis. However, the protective effects of neuronal NEP expression on intraneuronal Abeta42 accumulation and neurodegeneration remain elusive. In contrast, sustained NEP activation may be detrimental because NEP can degrade many physiological peptides, but its consequences in the brain are not fully understood. Using transgenic Drosophila expressing human NEP and Abeta42, we demonstrated that NEP efficiently suppressed the formation of intraneuronal Abeta42 deposits and Abeta42-induced neuron loss. However, neuronal NEP overexpression reduced cAMP-responsive element-binding protein-mediated transcription, caused age-dependent axon degeneration, and shortened the life span of the flies. Interestingly, the mRNA levels of endogenous fly NEP genes and phosphoramidon-sensitive NEP activity declined during aging in fly brains, as observed in mammals. Taken together, these data suggest both the protective and detrimental effects of chronically high NEP activity in the brain. Down-regulation of NEP activity in aging brains may be an evolutionarily conserved phenomenon, which could predispose humans to developing late-onset AD.
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