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Dynamic Nature of presenilin1/?-Secretase: Implication for Alzheimer's Disease Pathogenesis.


ABSTRACT: Presenilin 1 (PS1) is a catalytic component of the ?-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The ?-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid ? (A?) species. The assembly of A? into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relative ratio of the longer (A?42/43) to shorter A? (A?40) peptides. The ratio of A?42 to A?40 depends on the conformation and activity of the PS1/?-secretase enzymatic complex. The latter exists in a dynamic equilibrium of the so called "closed" and "open" conformational states, as determined by the Förster resonance energy transfer (FRET)-based PS1 conformation assay. Here we review several factors that can allosterically influence conformational status of the enzyme, and hence the production of A? peptides. These include genetic variations in PS1, APP and other ?-secretase components, environmental stressors implicated in AD pathogenesis and pharmacological agents. Since "closed" PS1 conformation is the common outcome of many AD-related insults, the novel assays monitoring PS1 conformation in live/intact cells in vivo and in vitro might be utilized for diagnostic purposes and for validation of the potential therapeutic approaches.

SUBMITTER: Zoltowska KM 

PROVIDER: S-EPMC5610083 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.

Zoltowska Katarzyna Marta KM   Berezovska Oksana O  

Molecular neurobiology 20170322 3


Presenilin 1 (PS1) is a catalytic component of the γ-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The γ-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid β (Aβ) species. The assembly of Aβ into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relati  ...[more]

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