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.
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| http://dx.doi.org/10.1186/s40478-024-01876-y | DOI Listing |
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PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.
Acta Neuropathol Commun
October 2024
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
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.
View Article and Find Full Text PDFIdentification of PS1/gamma-secretase and glutamate transporter GLT-1 interaction sites.
J Biol Chem
April 2024
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. Electronic address:
Article Synopsis
- - Recent research has identified a crucial interaction between Presenilin 1 (PS1) and the glutamate transporter GLT-1, which connects their roles in Alzheimer's disease (AD) pathology, highlighting the need to explore how this interaction affects disease processes.
- - The study utilized an alanine scanning method and FRET-based fluorescence microscopy to pinpoint specific interaction sites between PS1 and GLT-1, discovering that specific residues on both proteins are essential for their binding.
- - To investigate the effects of this interaction in primary neurons, cell-permeable peptides targeting PS1 and GLT-1 were created, successfully reducing their interaction and providing a new tool for studying their functional relationship in both normal brain function and AD.
The recently discovered interaction between presenilin 1 (PS1), a catalytic subunit of γ-secretase responsible for the generation of amyloid-β(Aβ) peptides, and GLT-1, the major glutamate transporter in the brain (EAAT2 in the human) may provide a mechanistic link between two important pathological aspects of Alzheimer's disease (AD): abnormal Aβoccurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based approach, fluorescence lifetime imaging microscopy (FLIM), to characterize the PS1/GLT-1 interaction in its native environment in the brain tissue of sporadic AD (sAD) patients. There was significantly less interaction between PS1 and GLT-1 in sAD brains, compared to tissue from patients with frontotemporal lobar degeneration (FTLD), or non-demented age-matched controls.
View Article and Find Full Text PDFThe recently discovered interaction between Presenilin 1 (PS1), a catalytic subunit of γ-secretase responsible for generating amyloid-β (Aβ) peptides, and GLT-1, a major glutamate transporter in the brain (EAAT2) provides a mechanistic link between these two key factors involved in Alzheimer's disease (AD) pathology. Modulating this interaction can be crucial to understand the consequence of such crosstalk in AD context and beyond. However, the interaction sites between these two proteins are unknown.
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