Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene

Mullan, Michael; Tsuji, Shoji; Miki, Tetsuro; Katsuya, Tomohiro; Naruse, Satoshi; Kaneko, Kiyotoshi; Shimizu, Teruo; Kojima, Takeshi; Nakano, Imaharu; Ogihara, Toshio; Miyatake, Tadashi; Ovenstone, I.; Crawford, Fiona; Goate, Alison M.; Hardy, John; Roques, P; Roberts, George T.; Luthert, Philip J.; Lantos, Peter L.; Clark, Chris; Gaskell, P. C.; Crain, Barbara J.; Roses, A.D.

doi:10.1016/0197-4580(93)90099-w

Cited by 82 publications

(55 citation statements)

References 32 publications

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“…1 c-e). That expression of V642I-mutant hAPP695 per se did not induce apoptosis of differentiated B103 cells in the absence of other apoptosisinducing challenges is consistent with the fact that humans carrying FAD mutations live normally for decades before developing overt neurological disease (8,41,42).…”

Section: Resultsmentioning

confidence: 48%

Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis

Yang

Wyss‐Coray

et al. 1999

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

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Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abundance in brain and the association of various APP missense mutations with autosomal dominant forms of familial Alzheimer's disease (FAD) suggest important roles for APP in the central nervous system. However, the basic functions of APP in the central nervous system remain largely unknown. To assess potential effects of APP on neuronal death and survival, we transfected APP-deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild-type or FAD-mutant human APP. Wild-type, but not FAD-mutant, APP effectively protected cells against apoptosis induced by ultraviolet irradiation, staurosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, whereas FAD-mutant APP did not. We conclude that APP protects neuronal cells against apoptosis by controlling p53 activation at the post-translational level. Disruption of this function by mutations or alterations in APP processing could enhance neuronal vulnerability to secondary insults and contribute to neuronal degeneration.

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Section: Resultsmentioning

confidence: 48%

Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis

Yang

Wyss‐Coray

et al. 1999

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

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“…Expression of the APP V717I -CT100 transgene was associated with deposition of A␤ in the form of diffuse, noncongophilic extracellular plaques from 6 months of age. As in humans bearing the APP V717I mutation (36), a preponderance of the A␤ 1-42 isoform was identified. The combined tau V337M ϫ APP V717I -CT100 mice showed very similar spatial patterns of A␤ burden, extracellular plaque formation, and phospho-tau and neurofibrillary tangle formation when compared to the single transgenic strains.…”

Section: Discussionmentioning

confidence: 98%

“…For the AD model, we expressed the familial AD V717I (valine to isoleucine) "London" mutation (13) within a 100-amino-acid carboxy-terminal (C-terminal) fragment of the human amyloid precursor protein (APP-CT100), which encompasses the ␤ amyloid (A␤) sequence (6). The APP V717I substitution is associated with an aggressive early-onset dementia and a characteristic increase in the long amyloidogenic form of A␤ (A␤ ) in AD brain (36).…”

Section: Abnormal Tau Phosphorylation Occurs In Several Neurodegeneramentioning

confidence: 99%

Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities

Lambourne

Sellers

Bush

et al. 2005

Molecular and Cellular Biology

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Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tau V337M ) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a "combined" model, expressing both tau V337M and the familial amyloid precursor protein AD mutation APP V717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau V337M mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH 2 -terminal kinase) but not glycogen synthase kinase-3␣␤ or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP V717I -CT100 transgene expression as near identical changes were observed in single APP V717I -CT100 mice. Age-dependent deficits in memory were also associated with tau V337M and APP V717I -CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.

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“…The Aβ amyloid in SP is derived from a larger amyloid precursor protein (APP), the gene of which is located on chromosome 21 [12]. Mutations at codons 717 and 670/671 of the APP gene have been identified in familial early onset AD [5,9,23,24]. APP mutations have been reported as rare genetic causes of presenile familial AD [30].…”

Section: Introductionmentioning

confidence: 99%

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

Cras

Hendriks

Ceuterick

et al. 1998

Acta Neuropathologica

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Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer's disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala→ Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Aβ amyloid protein. Numerous senile plaques consisted of large Aβ amyloid cores, often measuring more than 30 µ m in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly

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Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene

Cited by 82 publications

References 32 publications

Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis

Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis

Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

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