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Titel: Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion
VerfasserIn: Barbero-Camps, Elisabet
Roca-Agujetas, Vicente
Bartolessis, Isabel
de Dios, Cristina
Fernández-Checa, Jose C.
Marí, Montserrat
Morales, Albert
Hartmann, Tobias
Colell, Anna
Sprache: Englisch
Titel: Autophagy
Bandnummer: 14
Heft: 7
Startseite: 1129
Endseite: 1154
Verlag/Plattform: Taylor & Francis
Erscheinungsjahr: 2018
Freie Schlagwörter: 2-hydroxypropyl-β-cyclodextrin
Alzheimer disease
ATG4B
autophagy
glutathione
oxidative stress
SNARE proteins
DDC-Sachgruppe: 570 Biowissenschaften, Biologie
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Macroautophagy/autophagy failure with the accumulation of autophagosomes is an early neuropathological feature of Alzheimer disease (AD) that directly affects amyloid beta (Aβ) metabolism. Although loss of presenilin 1 function has been reported to impair lysosomal function and prevent autophagy flux, the detailed mechanism leading to autophagy dysfunction in AD remains to be elucidated. The resemblance between pathological hallmarks of AD and Niemann-Pick Type C disease, including endosome-lysosome abnormalities and impaired autophagy, suggests cholesterol accumulation as a common link. Using a mouse model of AD (APP-PSEN1-SREBF2 mice), expressing chimeric mouse-human amyloid precursor protein with the familial Alzheimer Swedish mutation (APP695swe) and mutant presenilin 1 (PSEN1-dE9), together with a dominant-positive, truncated and active form of SREBF2/SREBP2 (sterol regulatory element binding factor 2), we demonstrated that high brain cholesterol enhanced autophagosome formation, but disrupted its fusion with endosomal-lysosomal vesicles. The combination of these alterations resulted in impaired degradation of Aβ and endogenous MAPT (microtubule associated protein tau), and stimulated autophagy-dependent Aβ secretion. Exacerbated Aβ-induced oxidative stress in APP-PSEN1-SREBF2 mice, due to cholesterol-mediated depletion of mitochondrial glutathione/mGSH, is critical for autophagy induction. In agreement, in vivo mitochondrial GSH recovery with GSH ethyl ester, inhibited autophagosome synthesis by preventing the oxidative inhibition of ATG4B deconjugation activity exerted by Aβ. Moreover, cholesterol-enrichment within the endosomes-lysosomes modified the levels and membrane distribution of RAB7A and SNAP receptors (SNAREs), which affected its fusogenic ability. Accordingly, in vivo treatment with 2-hydroxypropyl-β-cyclodextrin completely rescued these alterations, making it a potential therapeutic tool for AD.
DOI der Erstveröffentlichung: 10.1080/15548627.2018.1438807
URL der Erstveröffentlichung: https://www.tandfonline.com/doi/full/10.1080/15548627.2018.1438807
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-370028
hdl:20.500.11880/33578
http://dx.doi.org/10.22028/D291-37002
ISSN: 1554-8635
1554-8627
Datum des Eintrags: 5-Aug-2022
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Neurologie und Psychiatrie
Professur: M - Prof. Dr. Tobias Hartmann
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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