Alzheimer Disease: Iijima K

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.

Iijima K. · Akita University. · Kaibogaku Zasshi. · Pubmed #10659576 No free full text.

Abstract: The production and coexistence of neurotransmitters in the locus coeruleus is reviewed. Immunocytochemical and in situ hybridization evidence demonstrated that the LC consists mainly of a single cell population that is producing GABA and 5-HT in addition to noradrenaline (NA) simultaneously in single neurons. The coexistence of GABA, 5-HT and NA in single LC neurons was proved by identifying the same neurons in adjacent sections alternately immunostained by different antisera. In situ hybridization detected the signals of glutamic acid decarboxylase mRNA and tryptophan hydroxylase mRNA indicating the presence of GABA/GAD system and the ability to produce 5-HT in many LC neurons. Neuroanatomical studies strongly suggest that a single NA cell population produces multiple transmitters so that the LC can play a role in mechanism controlling the human's adaptation to environmental changes. The present author introduces three different recent works concerning the LC. Caffé concluded that the concept of a NA-ergic cell population in all mammals is questionable. In similar cases to the domestic pig's LC, acetylcholinesterase activity, muscarinic and nicotinic receptor proteins should be checked. Tohyama et al. examined various receptor proteins in the LC and found localization of GAGAA, glutamate and glycine receptors. Maeda et al. reported that doaminergic neurons in the hypothalamus play a powerful role in mechanisms controlling the activity of NA-ergic neurons in the LC. Senile dementia of Alzheimer type causes marked atrophy and cell loss in the LC as well as the frontal lobe of the cerebrum. Molecular biology of the cell has been devoted to clarify the pathology of this fatal disease.

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.

Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y. · Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. · Proc Natl Acad Sci U S A. · Pubmed #15069204 links to  free full text

Abstract: Accumulation of amyloid-beta (Abeta) peptides in the brain has been suggested to be the primary event in sequential progression of Alzheimer's disease (AD). Here, we use Drosophila to examine whether expression of either the human Abeta40 or Abeta42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of Abeta42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of Abeta40 caused only age-dependent learning defects but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggest that accumulation of Abeta42 in the brain is sufficient to cause behavioral deficits and neurodegeneration. Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying Abeta toxicity and the discovery of novel therapeutic targets for AD.

Taru H, Iijima K, Hase M, Kirino Y, Yagi Y, Suzuki T. · Laboratory of Neurobiophysics, School of Pharmaceutical Sciences, the University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. · J Biol Chem. · Pubmed #11912189 links to  free full text

Abstract: We have isolated a novel protein based on its association with Drosophila APP-like protein (APPL), a homolog of the beta-amyloid precursor protein (APP) that is implicated in Alzheimer's disease. This novel APPL-interacting protein 1 (APLIP1) contains a Src homology 3 domain and a phosphotyrosine interaction domain and is expressed abundantly in neural tissues. The phosphotyrosine interaction domain of APLIP1 interacts with a sequence containing GYENPTY in the cytoplasmic domain of APPL. APLIP1 is highly homologous to the carboxyl-terminal halves of mammalian c-Jun NH(2)-terminal kinase (JNK)-interacting protein 1b (JIP1b) and 2 (JIP2), which also contain Src homology 3 and phosphotyrosine interaction domains. The similarity of APLIP1 to JIP1b and JIP2 includes interaction with component(s) of the JNK signaling pathway and with the motor protein kinesin and the formation of homo-oligomers. JIP1b interacts strongly with the cytoplasmic domain of APP (APPcyt), as APLIP1 does with APPL, but the interaction of JIP2 with APPcyt is weak. Overexpression of JIP1b slightly enhances the JNK-dependent threonine phosphorylation of APP in cultured cells, but that of JIP2 suppresses it. These observations suggest that the interactions of APP family proteins with APLIP1, JIP1b, and JIP2 are conserved and play important roles in the metabolism and/or the function of APPs including the regulation of APP phosphorylation by JNK. Analysis of APP family proteins and their associated proteins is expected to contribute to understanding the molecular process of neural degeneration in Alzheimer's disease.

Ando K, Oishi M, Takeda S, Iijima K, Isohara T, Nairn AC, Kirino Y, Greengard P, Suzuki T. · Laboratory of Neurobiophysics, School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033 Japan. · J Neurosci. · Pubmed #10341243 links to  free full text

Abstract: Alzheimer's amyloid precursor protein (APP), the precursor of beta-amyloid (Abeta), is an integral membrane protein with a receptor-like structure. We recently demonstrated that the mature APP (mAPP; N- and O-glycosylated form) is phosphorylated at Thr668 (numbering for APP695 isoform), specifically in neurons. Phosphorylation of mAPP appears to occur during, and after, neuronal differentiation. Here we report that the phosphorylation of mAPP begins 48-72 hr after treatment of PC12 cells with NGF and that this correlates with the timing of neurite outgrowth. The phosphorylated form of APP is distributed in neurites and mostly in the growth cones of differentiating PC12 cells. PC12 cells stably expressing APP with Thr668Glu substitution showed remarkably reduced neurite extension after treatment with NGF. These observations suggest that the phosphorylated form of APP may play an important role in neurite outgrowth of differentiating neurons.

Watanabe T, Sukegawa J, Sukegawa I, Tomita S, Iijima K, Oguchi S, Suzuki T, Nairn AC, Greengard P. · Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York 10021, USA. · J Neurochem. · Pubmed #9930726 No free full text.

Abstract: Alzheimer amyloid precursor protein (APP) is an integral membrane protein with a short cytoplasmic domain of 47 amino acids. It is hoped that identification of proteins that interact with the cytoplasmic domain will provide new insights into the physiological function of APP and, in turn, into the pathogenesis of Alzheimer's disease. To identify proteins that interact with the cytoplasmic domain of APP, we employed affinity chromatography using an immobilized synthetic peptide corresponding to residues 645-694 of APP695 and identified a protein of approximately 130 kDa in rat brain cytosol. Amino acid sequencing of the protein revealed the protein to be a rat homologue of monkey UV-DDB (UV-damaged DNA-binding protein, calculated molecular mass of 127 kDa). UV-DDB/p127 co-immunoprecipitated with APP using an anti-APP antibody from PC12 cell lysates. APP also co-immunoprecipitated with UV-DDB/p127 using an anti-UV-DDB/p127 antibody. These results indicate that UV-DDB/p127, which is present in the cytosolic fraction, forms a complex with APP through its cytoplasmic domain. In vitro binding experiments using a glutathione S-transferase-APP cytoplasmic domain fusion protein and several mutants indicated that the YENPTY motif within the APP cytoplasmic domain, which is important in the internalization of APP and amyloid beta protein secretion, may be involved in the interaction between UV-DDB/p127 and APP.