A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid

Mullan, Mike; Crawford, Fiona; Axelman, Karin; Houlden, Henry; Lilius, Lena; Winblad, Bengt; Lannfelt, Lars

doi:10.1038/ng0892-345

Cited by 1,374 publications

(750 citation statements)

References 22 publications

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“…Overexpression of MDMX rescued cortical neurons from apoptosis induced by a mutated form of APP (APPSW 31 ) described in Alzheimer patients or by treatment with the APP-Ab (Figure 8f). These data suggest that APP affects neuronal viability in part by downregulating MDMX, which acts as a survival factor in diverse types of neurons and against various stress signals, through inhibition of p53 and/or E2F-1 activities.…”

Section: Resultsmentioning

confidence: 93%

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid b precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.

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Section: Resultsmentioning

confidence: 93%

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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“…The correlation of genetic mutations in early-onset AD pedigrees, particularly APP and the PSEN genes, with increased Aβ levels indicates amyloidogenic processing of APP may indeed be causative [10,13,23,29]. These and other mutations [33] that result in elevated Aβ production, carried out by β-secretase and γ-secretase, provide insight into how modulation of APP processing may be instrumental in AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The generation and deposition of Aβ peptides in the AD brain is hypothesized to be the causative phenomenon in AD pathogenesis. This hypothesis, known as the amyloid cascade, is corroborated genetically by the presence of familial AD mutations in the APP gene [10,13,29] that shift the processing of the APP holoprotein towards β-secretase cleavage, resulting in the increase of Aβ levels accompanied by a decrease of the non-amyloidogenic and non-pathogenic p3 peptide generated by the other APP holoprotein secretase, known as α-secretase [5,11]. Aβ metabolism can also be altered by many additional pathways including Aβ degradation, clearance, transport and aggregation [29].…”

Section: Introductionmentioning

confidence: 94%

“…This hypothesis, known as the amyloid cascade, is corroborated genetically by the presence of familial AD mutations in the APP gene [10,13,29] that shift the processing of the APP holoprotein towards β-secretase cleavage, resulting in the increase of Aβ levels accompanied by a decrease of the non-amyloidogenic and non-pathogenic p3 peptide generated by the other APP holoprotein secretase, known as α-secretase [5,11]. Aβ metabolism can also be altered by many additional pathways including Aβ degradation, clearance, transport and aggregation [29]. Nevertheless, the accumulation and aggregation of Aβ progresses in an age-related brain-regional pattern [3], but it is unknown how this pattern of age-dependent Aβ production and deposition is regulated.…”

Section: Introductionmentioning

confidence: 94%

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Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Chiocco

Lamb

2007

Neurobiology of Aging

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Genetic mutations associated with Alzheimer's disease (AD) in the Amyloid Precursor Protein (APP) gene specifically alter the production of the APP processing product, amyloid-β (Aβ) peptide, generated by β-and γ-secretases. The accumulation and deposition of Aβ is hypothesized to cause AD pathogenesis, leading to the debilitating neurological deficits observed in AD patients. However, it is unclear how processing of APP to generate Aβ corresponds with the age-dependent pattern of brain-regional neurodegeneration common in AD. We have previously shown that overexpression of BACE1, the primary β-secretase gene, in mice expressing an AD mutant form of APP leads to significantly elevated regional Aβ levels, which coincide with the regional pattern of Aβ deposition. In the current study, we have used our genomic-based β-secretase transgenic mice to determine how BACE1 regulates the spatial and temporal pattern of Aβ production throughout post-natal development. Specifically, we observed unique differences in the brain-regional expression pattern between neonatal and adult BACE1 transgenic mice. These alterations in the BACE1 expression profile directly corresponds with age-related differences in regional Aβ production and deposition. These studies indicate that modulation of BACE1 expression leads to dramatic alterations in APP processing and AD-like neuropathology. Furthermore, our studies provide further evidence that BACE1 plays a major role in the regulation of the APP processing pathway, influencing the agedependent onset of AD pathogenesis.

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“…Murrel et al, 1992;Chartier-Harlin et aI., 1992). Following reports showed the evidence for other kinds of mutations in exon 16 or 17 of APP gene segregating with some types of familial Alzheimer's disease (FAD) (Hendriks et al, 1992;Mullan et al, 1992;Balbin et al, 1992). Thus implications of mutation in APP gene and presumable unusual metabolic pathway of APP are now in the spotlight for the pathogenesis of a proportion of cases with FAD.…”

Section: Introductionmentioning

confidence: 99%

No evidence for a point mutation at codon 713 and 717 of amyloid precursor protein gene in Japanese schizophrenics

et al. 1993

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SummaryA point mutation at codon 717 of amyloid precursor protein (APP) gene has been demonstrated to play an important pathogenic role in some cases of familial Alzheimer's disease (FAD). Recently, a single case of chronic schizophrenia with a point mutation at codon 713 of APP gene which sits very close to the mutation in FAD was reported. We screened for these two kinds of mutations in 39 schizophrenic patients using polymerase chain reaction (PCR) and restriction enzyme technique. A mutation of codon 713 creates a MaelII restriction site and that of codon 717 creates a BclI site. Enzyme digestion with amplified PCR product revealed no restriction site in all subjects. None of our subjects had either of these two kinds of mutations. Our findings support the hypothesis that the case of a mutation at codon 713 of APP gene is a natural non-pathogenic variant and, as well as a mutation at codon 717, has no relation with the genetic predisposition to schizophrenia.

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A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid

Cited by 1,374 publications

References 22 publications

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

No evidence for a point mutation at codon 713 and 717 of amyloid precursor protein gene in Japanese schizophrenics

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