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- Sogorb-Esteve, A., et al.
(författare)
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Inhibition of gamma-Secretase Leads to an Increase in Presenilin-1
- 2018
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 55:6, s. 5047-5058
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer's disease (AD); however, trials have proven disappointing. We addressed the possibility that gamma-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic gamma-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other gamma-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained gamma-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development.
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| 2. |
- Sogorb-Esteve, A., et al.
(författare)
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Levels of ADAM10 are reduced in Alzheimer's disease CSF
- 2018
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: The disintegrin metalloproteinase 10 (ADAM10) is the main alpha-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein. This study assesses whether ADAM10 is present in cerebrospinal fluid (CSF), and whether it has potential as a biomarker for Alzheimer's disease (AD). Methods: ADAM10 was characterized in human CSF samples by immunoprecipitation and western blotting using antibodies specific for different domains of the protein and by ultracentrifugation in sucrose density gradients. Samples from AD patients (n = 20) and age-matched non-AD controls (n = 20) were characterized for classical CSF biomarkers, A beta 42, T-tau, or P-tau by ELISA, and assayed for soluble ADAM10 levels by western blotting. Results: We found that ADAM10 is present in human CSF as several distinct species: an immature form retaining the prodomain (proADAM10; similar to 80 kDa), a mature unprocessed full-length form (ADAM10f; similar to 55 kDa), and a truncated large soluble form released from the membrane (sADAM10; similar to 50 kDa). Fractionation by ultracentrifugation on sucrose density gradients showed that the ADAM10f and sADAM10 species form large complexes. Immunoblotting revealed a significant decrease in ADAM10f and sADAM10 in AD CSF compared to control CSF, while proADAM10 levels remained unaltered. Conclusions: Several forms of ADAM10 are present in CSF, mainly assembled as high-molecular weight complexes. The determination of the levels of mature forms of CSF-ADAM10 may be useful as a biomarker for AD.
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