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

Moehlmann, T.; Winkler, Edith; Xia, Xuefeng; Edbauer, Dieter; Murrell, Jill R.; Capell, Anja; Kaether, Christoph; Zheng, Hui; Ghetti, Bernardino; Haass, Christian; Steiner, Harald

doi:10.1073/pnas.112686799

Cited by 257 publications

(234 citation statements)

References 43 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, our results indicate that different amino acid substitutions at the same residue of PS1 can cause distinct modifications of ␥-secretase activity. These results confirm and extend previous studies showing that several mutations at residue 166 or 384 differentially affect the secreted A␤ level and the A␤ 42 /total A␤ ratio (16,18). These observations suggest that the effect of PS mutations on the ␥-secretase activity and specificity is not mediated by simple loss of function of a restricted domain or motif.…”

Section: Discussionsupporting

confidence: 81%

“…The next lowest activity state is typified by the PS1 LA mutants, in which there is residual self-endoproteolysis, ␥-40 cleavage, and ⑀-cleavage, but relatively high ␥-42/43 activity. Another stage of activity, generally supporting normal self-endoproteolysis and ␥-40 activity, but reduced ⑀-cleavage and enhanced ␥-42/43 activity, is represented by many FAD mutants (5,18,33). Finally, WT-PS1 represents the fully functional state, wherein PS1 supports self-endoproteolysis, ⑀-cleavage, predominant ␥-40 activity, and minor ␥-42/43 activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Nakaya

Yamane

Shiraishi

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid ␤-peptides (A␤ 42/43 ) by altering ␥-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate ␥-secretase cleavage of the amyloid ␤-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A␤ 43 , but did not support physiological PS1 endoproteolysis or A␤ 40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A␤ 43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of ␥-secretase and that the effects of PS1 mutations and ␥-secretase inhibitors on the specificity are mediated through a common mechanism.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Nakaya

Yamane

Shiraishi

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Several PS1 mutations that increase the production of A␤42 were found to reduce Notch site 3 cleavage (24, 26 -29) and production of CTF␥ as well (24,29). These results are consistent with the present quantitative data based on sequencing, showing that the total amounts of CTF␥ produced in the mtPS2 membranes are reduced to ϳ50% of those of wtPS2 membranes (Table I).…”

Section: Figsupporting

confidence: 82%

Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49–99 of β-Amyloid Precursor Protein

Sato

Dohmae

et al. 2003

Journal of Biological Chemistry

Self Cite

144

159

View full text Add to dashboard Cite

A novel cleavage of ␤-amyloid precursor protein (APP), referred to as ⑀-cleavage, occurs downstream of the ␥-cleavage and generates predominantly a C-terminal fragment (CTF␥) that begins at Val-50, according to amyloid ␤-protein (A␤) numbering. Whether this cleavage occurs independently of, or is coordinated with, ␥-cleavage is unknown. Using a cell-free system, we show here that, although A␤40 and CTF␥ 50 -99 were the predominant species produced by membranes prepared from cells overexpressing wild-type (wt) APP and wt presenilin (PS) 1 or 2, the production of CTF␥ 49 -99, which begins at Leu-49, was remarkably enhanced in membranes from cells overexpressing mutant (mt) APP or mtPS1/2 that increases the production of A␤42. Furthermore, a ␥-secretase inhibitor, which suppresses A␤40 production and paradoxically enhances A␤42 production at low concentrations, caused the proportion of CTF␥ 50 -99 to decrease and that of CTF␥ 49 -99 to increase significantly. These results strongly suggest a link between the production of A␤42 and CTF␥ 49 -99 and provide an important insight into the mechanisms of altered ␥-cleavage caused by mtAPP and mtPS1/2.Senile plaques, one of the neuropathological hallmarks of Alzheimer's disease (AD), 1 are composed primarily of amyloid ␤-protein (A␤) (1). Two major A␤ species consisting of 40 and 42 residues are generated mainly in neurons and constitutively secreted. A shorter one, A␤40, is predominant, and a longer one, A␤42, is a minor species (Ͻ10%) among secreted A␤ species. A␤ is produced from ␤-amyloid precursor protein (APP), through sequential cleavage by proteases referred to as ␤-and ␥-secretases. ␤-Secretase was identified as a type I membrane aspartic protease ␤-site APP-cleaving enzyme (BACE) (2), but the identity of ␥-secretase has remained unknown. ␥-Secretase cleaves APP in the middle of the transmembrane domain, releasing A␤ and its counterpart, C-terminal fragment ␥ of APP (CTF␥). Most recent studies have shown that ␥-secretase forms a large complex composed of presenilin (PS) 1 or 2, nicastrin, PEN-2, and APH-1, and the activity of ␥-secretase is now known to depend on these proteins (3-7).One of the A␤ species, A␤42, has a much higher aggregation potential (8, 9) and is believed to be initially deposited in senile plaques (10). It is reasonable to postulate that A␤42 accumulation in the brain is the very initial event in the development of AD including sporadic AD. Indeed, all mutations of PS1/2 and some mutations of APP that cause familial AD result in increased A␤42 production (11).Recently, we and other groups found that APP is cleaved by PS-dependent ␥-secretase, not only in the middle of the transmembrane domain (␥-cleavage) but also near the cytoplasmic membrane boundary (⑀-cleavage) (12-15). The major product of the latter process is a CTF␥ of APP that begins at Val-50. This cleavage site is a few residues inside the membrane from the cytoplasmic/membrane boundary and is similar to site 3 cleavage of Notch (16). Since production of CTF␥ is inhibited by a dominan...

show abstract

“…Interestingly, the vast majority of PS mutations that impair NICD production also impair AICD production, indicating a general impairment of ␥-secretasedependent function that is not limited to a single substrate (Table 1) (11)(12)(13)(14)(15). This correspondence of the effects of mutations on liberation of NICD and AICD may reflect mechanistic similarities between the S3 and cleavages of Notch and APP, respectively, which occur at similar intramembranous positions near the cytoplasmic face of the plasma membrane.…”

Section: Fad-linked Ps Mutations Impairmentioning

confidence: 96%

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Shen

Kelleher

2007

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

427

358

View full text Add to dashboard Cite

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

show abstract

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

Cited by 257 publications

References 43 publications

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49–99 of β-Amyloid Precursor Protein

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Contact Info

Product

Resources

About

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

Cited by 257 publications

References 43 publications

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49–99 of β-Amyloid Precursor Protein

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Contact Info

Product

Resources

About

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