Familial Alzheimer's disease A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine → glycine)

Kennedy, Angus; Newman, Sarah; McCaddon, Andrew; Ball, J. K.; Roques, P; Mullan, Mike; Hardy, John; Chartier-Harlin, Marie-Christine; Frackowiak, R. S. J.; Warrington, E. K.; Rossor, Martin N.

doi:10.1093/brain/116.2.309

Cited by 65 publications

(18 citation statements)

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“…The first piece of evidence is provided by the identification of several point mutations within the APP gene. These mutations segregate within a subgroup of patients afflicted with a familial form of the disorder and thus suggest a pathogenetic relationship between the APP gene and AD (ChartierHarlin et al, 1991;Kennedy et al, 1993). Second, amyloid deposition temporally precedes the development of neurofibrillary changes (Pappolla and Robakis, 1995), and this observation is also consistent with a link between amyloid and neuronal degeneration.…”

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confidence: 86%

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

et al. 1997

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Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid ␤ protein (A␤) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca 2ϩ increases induced by a cytotoxic fragment of A␤. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

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confidence: 86%

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

et al. 1997

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“…APP mutations have been reported as rare genetic causes of presenile familial AD [30]. Most patients with APP mutations show a morphological picture that highly resembles sporadic AD, although the severity of the morphological changes is usually impressive [8,13,14,19]. In one single family, a patient showed cortical Lewy bodies in addition to neurofibrillary tangles (NFT) [16], while another showed a typical morphological picture of AD [4].…”

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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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“…A metalloproteinase related to the tumor necrosis factor-␣ converting enzyme (7,8) can cleave APP to sAPP␣ upon activation of PKC by phorbol esters 2 (9,10). Strong evidence that A␤ plays an important role in AD pathogenesis has come from the study of mutations in the APP (11)(12)(13)(14), presenilin 1 (15), and presenilin 2 (16) genes that are known to cause early onset familial AD (FAD) (17). A fundamental effect of all the FAD-linked mutations is to increase the concentration of A␤42 or of both A␤40 and A␤42 (18 -22).…”

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confidence: 99%

Glycosylphosphatidylinositol-anchored Proteins Play an Important Role in the Biogenesis of the Alzheimer's Amyloid β-Protein

Sambamurti

Sevlever

Koothan

et al. 1999

Journal of Biological Chemistry

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The Alzheimer's amyloid protein (A␤) is released from the larger amyloid ␤-protein precursor (APP) by unidentified enzymes referred to as ␤-and ␥-secretase. ␤-Secretase cleaves APP on the amino side of A␤ producing a large secreted derivative (sAPP␤) and an A␤-bearing C-terminal derivative that is subsequently cleaved by ␥-secretase to release A␤. Alternative cleavage of the APP by ␣-secretase at A␤16/17 releases the secreted derivative sAPP␣. In yeast, ␣-secretase activity has been attributed to glycosylphosphatidylinositol (GPI)-anchored aspartyl proteases. To examine the role of GPIanchored proteins, we specifically removed these proteins from the surface of mammalian cells using phosphatidylinositol-specific phospholipase C (PI-PLC). PI-PLC treatment of fetal guinea pig brain cultures substantially reduced the amount of A␤40 and A␤42 in the medium but had no effect on sAPP␣. A mutant CHO cell line (gpi85), which lacks GPI-anchored proteins, secreted lower levels of A␤40, A␤42, and sAPP␤ than its parental line (GPI؉). When this parental line was treated with PI-PLC, A␤40, A␤42, and sAPP␤ decreased to levels similar to those observed in the mutant line, and the mutant line was resistant to these effects of PI-PLC. These findings provide strong evidence that one or more GPI-anchored proteins play an important role in ␤-secretase activity and A␤ secretion in mammalian cells. The cell-surface GPI-anchored protein(s) involved in A␤ biogenesis may be excellent therapeutic target(s) in Alzheimer's disease.The amyloid that is invariably deposited in Alzheimer's disease (AD) 1 is composed of an approximately 4-kDa peptide (amyloid ␤-peptide, A␤) that is derived from a larger protein referred to as the amyloid ␤-protein precursor (APP) (1, 2). APP is a type I integral membrane glycoprotein with a large Nterminal extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. The A␤ peptide begins 99 amino acids from the C terminus of APP, and it extends from the extracellular region to a point half-way through the APP membrane-spanning domain (1). A␤ is released from APP by cleavage on its N-and C-terminal ends by ␤-and ␥-secretase, respectively. ␤-Secretase cleavage before residue 1 of A␤ (672 of APP770) also releases the secreted derivative sAPP␤, whereas an alternative cleavage before residue 17 by ␣-secretase releases sAPP␣. In most culture systems tested, the predominant cleavage product is sAPP␣, and this may serve to prevent the production of A␤ (1). The proteolytic processing of APP to sAPP and A␤ is regulated by protein kinase C (3), protein tyrosine kinase (4), muscarinic receptors (5), and estrogens (6). The regulatory pathways involved are cell type-dependent, have little or no effect in some cell types, and normally stimulate the secretion of sAPP␣ while simultaneously reducing the secretion of A␤ (2). A metalloproteinase related to the tumor necrosis factor-␣ converting enzyme (7,8) can cleave APP to sAPP␣ upon activation of PKC by phorbol esters 2 (9, 10). Strong evidence that A␤ plays...

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Familial Alzheimer's disease A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine → glycine)

Cited by 65 publications

References 0 publications

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

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

Glycosylphosphatidylinositol-anchored Proteins Play an Important Role in the Biogenesis of the Alzheimer's Amyloid β-Protein

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