β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity

Zheng, Hui; Jiang, Mingming; Trumbauer, Myrna E.; Sirinathsinghji, D.J.S.; Hopkins, Ruth; Smith, David W.; Heavens, R.P.; Dawson, Gerard R.; Boyce, Susan; Conner, Michael W.; Stevens, Karla; Slunt, Hilda H.; Sisodia, Sangram S.; Chen, Howard Y.; Ploeg, Lex H.T. Van der

doi:10.1016/0092-8674(95)90073-x

Cited by 636 publications

(470 citation statements)

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“…Two specifically immunoreactive AICD proteins, a major band of Ϸ5 kDa and a minor band of Ϸ7 kDa, were routinely detected in freshly prepared brain homogenates with either antibody. Both these proteins were absent in the brains of mice lacking APP expression (40) and increased in the brains of transgenic mice overexpressing human APP (41) (Fig. 2A).…”

Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 97%

“…To characterize the role of IDE in A␤ metabolism in brain, the principal site of A␤ accumulation, we compared degradation of 100 pM 125 I-A␤ 40 in both soluble and Na 2 CO 3 -washed membrane fractions of brain from WT and IDE Ϫ͞Ϫ mice. TCA precipitation assays (see Materials and Methods) were performed at reaction times 0, 3, and 8 h for membranes and at 0, 30, and 60 min for soluble fractions.…”

Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 99%

“…To extend our finding of the IDE-mediated A␤-degradation deficit to intact, living neurons, the principal producers of A␤, we added 125 I-A␤ 40 (40 pM) to primary cortical neuronal cultures and performed TCA degradation assays. IDE Ϫ͞Ϫ neurons had Ϸ70 -90% less degradation of this extracellular A␤ than did WT neurons (P Ͻ 0.00001 for each time point; Fig.…”

Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 99%

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Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Farris

Mansourian

Chang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,340

1,040

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Two substrates of insulin-degrading enzyme (IDE), amyloid ␤-protein (A␤) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of A␤ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases A␤ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE ؊͞؊). IDE deficiency resulted in a >50% decrease in A␤ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE ؊͞؊ mice showed increased cerebral accumulation of endogenous A␤, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the ␤-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD. I nsulin-degrading enzyme (IDE, insulysin) is an Ϸ110-kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface (1-4) that cleaves small proteins of diverse sequence, many of which share a propensity to form ␤-pleated sheet-rich amyloid fibrils under certain conditions [e.g., amyloid ␤-protein (A␤), insulin, glucagon, amylin, atrial natriuretic factor, and calcitonin] (5, 6). IDE is the major enzyme responsible for insulin degradation in vitro (1), but the extent to which it mediates insulin catabolism in vivo has been controversial, with doubts expressed that IDE has any physiological role in insulin catabolism (7). Insulin, which is critical for glucose, lipid, and protein metabolism, as well as for cell growth and differentiation, is cleared mainly by the liver and kidney, but most other tissues also degrade the hormone. It was recently shown that transferring an Ϸ3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia (8). The GK allele of IDE in this chromosomal region was found to bear two missense mutations that, when transfected into COS-1 cells, resulted in 31% less insulin degradation compared with cells transfected with the WT allele. Furthermore, the IDE region of chromosome 10q has been genetically linked to DM2 (9, 10) and to elevated fasting glucose levels [20-year means (1...

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Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 97%

Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 99%

Section: Decreased A␤ Catabolism and In Vivo Accumulation Of A␤ In Idmentioning

confidence: 99%

See 1 more Smart Citation

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Farris

Mansourian

Chang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,340

1,040

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“…Deletion of the APP gene in mice resulted in neither early mortality, nor appreciable morbidity, although these mice exhibited reactive gliosis and changes in locomotor behavior [154]. The lack of vital consequence of APP deletion in vivo may result from the fact that mammals express proteins closely homologous to APP, the APP-like proteins (APLPs) [155].…”

Section: Transgenic Mouse Models For Eoadmentioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

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“…A mouse model that is deficient in ␤PP has been developed and exhibits phenotypic abnormalities including: reactive gliosis, a reduced forelimb grip strength, and decreased locomotion. 3 While the reasons underlying the phenotypic changes in the ␤PP-deficient mice have not been thoroughly explored, the model does argue that ␤PP is important for normal nervous system function. We began our investigations to determine the biology of neuronal ␤PP and have recently shown that ␤PP contributes to neuronal viability and neuron differentiation in vitro.…”

mentioning

confidence: 99%

When less says more: clues from a missing Alzheimer-associated protein

Perez

Koo

1998

Mol Psychiatry

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A knockout mouse model gives us clues regarding the important normal functions of both full-length and secreted fragments of the ␤-amyloid precursor protein in the central nervous system.In 1906 Alois Alzheimer examined the brain of a profoundly demented patient and observed the presence of intraneuronal fibrils (neurofibrillary tangles) and 'miliary foci of a peculiar substance in the cerebral cortex' (senile plaque). 1 Diagnosis of the disease, later named after Alzheimer, still rests on the identification of tangles and plaques in postmortem brain tissue. Although Alzheimer's disease (AD) was initially thought to be a rare disorder, it has become a serious public health issue. To understand the pathology of and to direct potential therapies for AD requires characterizing the major proteins associated with AD brain lesions. To this end, we are studying ␤-amyloid precursor protein (␤PP), the precursor to the ␤-amyloid (A␤) that is the major protein constituent of AD senile plaques.Because ␤PP is abundantly expressed in brain cells and because potential therapeutic strategies are aimed at altering ␤PP levels it is important to determine the physiological role of ␤PP in brain. Although many putative roles have been attributed to ␤PP (recently reviewed in Reference 2), 2 it is crucial to determine if diminishing ␤PP affects normal neuronal physiology. A mouse model that is deficient in ␤PP has been developed and exhibits phenotypic abnormalities including: reactive gliosis, a reduced forelimb grip strength, and decreased locomotion. 3 While the reasons underlying the phenotypic changes in the ␤PP-deficient mice have not been thoroughly explored, the model does argue that ␤PP is important for normal nervous system function. We began our investigations to determine the biology of neuronal ␤PP and have recently shown that ␤PP contributes to neuronal viability and neuron differentiation in vitro. 4 By comparing the survival of cultured hippocampal neurons from wild-type (WT) and ␤PP-deficient knockout (KO) mice, we determined that WT neurons survive better than do KO neurons in all culture conditions tested.Correspondence: RG Perez, PhD, Allegheny University of the Health Sciences, Center for Neuroscience Research, 10th Floor, South Tower, 320 E North Avenue, Pittsburgh, PA 15212, USA Because WT neurons express full-length ␤PP while KO neurons do not, and because the presence of different factors in the media did not rescue KO neurons to the same level as WT controls, it appears that neuron survival is enhanced by the expression of cell-associated full-length ␤PP.The advantage of using this unique model system is that it allows for selectively teasing apart the relative contributions of cell-associated ␤PP, on neurons, from the effects of soluble forms of ␤PP. To test for differences in process outgrowth in response to astrocytederived soluble factors we co-cultured WT and KO neurons with astrocytes obtained from WT or KO mice. WT (but not KO) astrocytes release soluble ␤PP fragments 5 including the long N-terminal fr...

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β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity

Cited by 636 publications

References 45 publications

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Genetics of Early-Onset Alzheimer Dementia

When less says more: clues from a missing Alzheimer-associated protein

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