PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.

Autor: Perrin F; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. fperrin@mgh.harvard.edu., Anderson LC; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Mitchell SPC; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Sinha P; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Turchyna Y; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Maesako M; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Houser MCQ; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA., Zhang C; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA., Wagner SL; Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA.; VA San Diego Healthcare System, La Jolla, CA, 92161, USA., Tanzi RE; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA., Berezovska O; Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. oberezovska@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Oct 21; Vol. 12 (1), pp. 166. Date of Electronic Publication: 2024 Oct 21.
DOI: 10.1186/s40478-024-01876-y
Abstrakt: The recently discovered interaction between presenilin 1 (PS1), a subunit of γ-secretase involved in amyloid-β (Aβ) peptide production, and GLT-1, the major brain glutamate transporter (EAAT2 in the human), may link two pathological aspects of Alzheimer's disease: abnormal Aβ occurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based fluorescence lifetime imaging microscopy (FLIM) to characterize the PS1/GLT-1 interaction in brain tissue from sporadic AD (sAD) patients. sAD brains showed significantly less PS1/GLT-1 interaction than those with frontotemporal lobar degeneration or non-demented controls. Familial AD (fAD) PS1 mutations, inducing a "closed" PS1 conformation similar to that in sAD brain, and gamma-secretase modulators (GSMs), inducing a "relaxed" conformation, respectively reduced and increased the interaction. Furthermore, PS1 influences GLT-1 cell surface expression and homomultimer formation, acting as a chaperone but not affecting GLT-1 stability. The diminished PS1/GLT-1 interaction suggests that these functions may not work properly in AD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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