γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

Serneels, Lutgarde; Biervliet, Jérôme Van; Craessaerts, Katleen; Dejaegere, Tim; Horré, Katrien; Houtvin, Tine Van; Esselmann, Hermann; Paul, Sabine; Schäfer, Martin K.; Berezovska, Oksana; Hyman, Bradley T.; Sprangers, Ben; Sciot, Raf; Moons, Lieve; Jucker, Mathias; Yang, Zhihui; May, Patrick C.; Karran, Eric; Wiltfang, Jens; D’Hooge, Rudi; Strooper, Bart De

doi:10.1126/science.1171176

Cited by 245 publications

(262 citation statements)

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“…The molecular mechanism that allows Aβ43 production but not other proteolytic processes remains to be clarified, but it is likely to involve specific conformational changes of the γ-secretase complex 37 . Because Aβ42 is produced independently of Aβ43 in the presence of γ-secretase, some of the FAD-associated PS1 mutations that cause a decrease in Aβ40 without an increase in Aβ42, such as A79V, A231V, C263F, L282V, L166P and G384A 24,38 , might actually result in the elevation of Aβ43 in a manner similar to the R278I mutation.…”

Section: Discussionmentioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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Section: Discussionmentioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…Inhibition of BACE1 activity by genetic (6)(7)(8) or pharmacologic (9-13) means strongly supports a therapeutic benefit demonstrating reductions in amyloid-b levels and rescued cognitive deficits in animal models, and several clinical trials of BACE inhibitors are under way (14). TG mice recapitulate certain features of Alzheimer disease, including amyloid-b deposition, gliosis, loss of dendritic spines, and cognitive deficits (15)(16)(17). Wild-type (WT) and TG mice underwent treatment with vehicle or BACE inhibitor, and outcome measures of amyloid pathology, brain function, and neuroinflammation were obtained through small-animal PET imaging with 18 F-FDG, 18 F-peripheral benzodiazepine receptor ( 18 F-PBR) 1, and 18 F-AV45, respectively.…”

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confidence: 99%

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

et al. 2017

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In this study, we investigated the effects of chronic administration of an inhibitor of the b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-b pathology were obtained through small-animal PET imaging with 18 F-FDG, 18 F-peripheral benzodiazepine receptor ( 18 F-PBR), and 18 F-florbetapir ( 18 F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18 F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-b (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18 F-AV45 uptake. An effect of treatment was observed in the cortex (P 5 0.0014), hippocampus (P 5 0.0005), and thalamus (P , 0.0001). Histology confirmed reduction of amyloid-b pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18 F-FDG uptake than WT mice in the thalamus (P 5 0.0004) and hippocampus (P 5 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18 F-PBR111 detected a significant age-related increase in TG mice (P , 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18 F-FDG, 18 F-PBR111, and 18 F-AV45 all detected pathologic alterations between TG and WT mice, only 18 F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18 F-AV45 undermine the specificity of this effect.

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“…These results suggest that the binding of the subunits renders the pore structure narrower to form an enzymatically active catalytic site within the pore. Supporting this notion, Fluorescence-lifetime imaging microscopic analysis revealed that the interaction with different isoforms of Aph-1 or mutant Pen-2 affected the distance between PS1 NTF and CTF (33,34). To date, several different functions of the ␥-secretase subunits have been suggested: activity modulation, substrate recognition, trafficking, and stabilization of the enzyme (35).…”

Section: Discussionmentioning

confidence: 75%

Contribution of the γ-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein

Takeo

Watanabe

Tomita

et al. 2012

Journal of Biological Chemistry

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Background: ␥-Secretase, which is composed of presenilin and three subunits, is an intramembrane-cleaving protease related to Alzheimer disease. Results: Water accessibility of the catalytic pore of presenilin was decreased during assembly of active ␥-secretase. Conclusion: Binding of the subunits allosterically contributes to the formation of catalytic pore. Significance: The ␥-secretase subunits modulate the structure of presenilin.

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γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

Cited by 245 publications

References 24 publications

Potent amyloidogenicity and pathogenicity of Aβ43

Potent amyloidogenicity and pathogenicity of Aβ43

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

Contribution of the γ-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein

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