Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease

Murayama, Ohoshi; Tomita, Taisuke; Nihonmatsu, Naomi; Murayama, Miyuki; Sun, Xiaoyan; Honda, Toshiyuki; Iwatsubo, Takeshi; Takashima, Akihiko

doi:10.1016/s0304-3940(99)00187-1

Cited by 122 publications

(104 citation statements)

References 14 publications

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“…Immunoprecipitates were separated on a previously described gel system, which allowed the specific detection and quantitation of both A␤ species (56). Consistent with previous results (33,68) this revealed that the FADassociated PS1 L286V mutation increased the A␤42/A␤40 levels (Fig. 6a).…”

Section: Sel-12 C60s and Ps1 C92s Facilitate Notch1supporting

confidence: 86%

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

Okochi

Eimer

Böttcher

et al. 2000

Journal of Biological Chemistry

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The familial Alzheimer's disease-associated presenilins (PSs) occur as a dimeric complex of proteolytically generated fragments, which functionally supports endoproteolysis of Notch and the ␤-amyloid precursor protein (␤APP). A homologous gene, sel-12, has been identified in Caenorhabditis elegans. We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteolytic cleavage in C. elegans similar to the PSs in human tissue. In contrast, SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon expression in human cells, suggesting that SEL-12 is cleaved by a C. elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not associated with a dominant negative activity in human cells, because SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere with Notch1 cleavage. Moreover, both mutant variants increase the aberrant production of the highly amyloidogenic 42-amino acid version of amyloid ␤-peptide similar to familial Alzheimer's disease-associated human PS mutants. Our data therefore demonstrate that the C60S mutation in SEL-12 is associated with aberrant endoproteolysis and a loss of function in C. elegans, whereas a gain of misfunction is observed upon expression in human cells.

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Section: Sel-12 C60s and Ps1 C92s Facilitate Notch1supporting

confidence: 86%

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

Okochi

Eimer

Böttcher

et al. 2000

Journal of Biological Chemistry

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“…A rather strong increase in the A␤ 42 ͞ A␤ total ratio was also observed for the serine and alanine substitutions. In contrast, the cysteine and tryptophan substitutions elevated the A␤ 42 ͞A␤ total ratio only slightly, similar to the majority of the known PS1 mutations (37). Thus, all artificial L166 mutants described here induce pathological A␤ 42 production and may therefore probably lead to AD if they occur in humans.…”

Section: Resultssupporting

confidence: 59%

“…11 and 36; Fig. 1D) and considerably higher than that found for the large majority of the PS1 mutations (37).…”

Section: Resultsmentioning

confidence: 63%

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Moehlmann

Winkler

Xia

et al. 2002

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

257

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“…Furthermore, transfected cell lines may not be the best method for assessing whether A␤42 levels are increased in response to the Glu318Gly mutation, as it has been shown that other PS-1 mutations which are associated with varying degrees of clinical severity as determined by their ages of onset, do not exhibit corresponding differences in A␤42 production in transfected cell lines. 29,30 Further studies with skin fibroblasts from individuals with the Glu318Gly mutation need to be undertaken to determine whether this mutation results in increased A␤42 levels as has been shown for other PS-1 mutations. 31 …”

Section: Discussionmentioning

confidence: 99%

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

et al. 2002

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Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of earlyonset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-⑀4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P Ͻ 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

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Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease

Cited by 122 publications

References 14 publications

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

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Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease

Cited by 122 publications

References 14 publications

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

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Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production