Research Article: Allosteric Modulation of PS1/γ-Secretase Conformation Correlates with Amyloid β42/40 Ratio

Date Published: November 18, 2009

Publisher: Public Library of Science

Author(s): Kengo Uemura, Christina M. Lill, Xuejing Li, Jessica A. Peters, Alexander Ivanov, Zhanyun Fan, Bart DeStrooper, Brian J. Bacskai, Bradley T. Hyman, Oksana Berezovska, Hitoshi Okazawa.

Abstract: Presenilin 1(PS1) is the catalytic subunit of γ-secretase, the enzyme responsible for the Aβ C-terminal cleavage site, which results in the production of Aβ peptides of various lengths. Production of longer forms of the Aβ peptide occur in patients with autosomal dominant Alzheimer disease (AD) due to mutations in presenilin. Many modulators of γ-secretase function have been described. We hypothesize that these modulators act by a common mechanism by allosterically modifying the structure of presenilin.

Partial Text: γ-Secretase is an enzymatic complex composed of at least four proteins: presenilin 1 or presenilin 2 (PS1 or PS2), Nicastrin, Pen2 and Aph1 [1]–[5], with presenilin representing the catalytic core [6]–[9]. Change in the precision of the APP substrate cleavage by γ-secretase result in change in the Aβ42/40 ratio. Aβ42 represents a highly fibrillogenic species that is more prone to form neurotoxic oligomers leading to synaptic dysfunction and neuronal death [10], [11]. An increase in the Aβ42/40 ratio has been implicated in Alzheimer’s disease (AD) pathogenesis. However, it remains unclear what cellular and molecular factors are responsible for the shift in APP γ-cleavage site towards toxic Aβ42 species.

An aggregation and deposition of amyloid β (Aβ) containing plaques is a common feature of normal aging and the AD brain. A shift towards an increased proportion of the longer, highly fibrillogenic and neurotoxic Aβ species (i.e., Aβ42) in the brain has been associated with the neurodegeneration leading to AD. Blocking Aβ production can be a therapeutic target. However, direct inhibition of γ-secretase activity may cause undesirable side effects due to disruption of the normal physiological function of numerous γ-secretase substrates, including APP itself [26] and Notch [27]. Instead, modulators of the site at which γ−secretase cleaves APP have been developed by screening libraries of compounds, or noted by genetic manipulations [13], [17], [25]. However, the precise molecular and cellular mechanism underlying the resultant changes in the Aβ42/40 ratio is unknown. We propose a hypothesis of “structure-function correlation” implying that structural changes in the PS1/γ-secretase are linked to the precision of γ-cleavage of APP to yield Aβ species of different lengths. Our data suggest that changes in the structure of multiple members of the γ-secretase complex, or even APP itself, can allosterically impact PS1 conformation in a way that leads to a change in γ-secretase/APP interactions and alters the exact cleavage site of APP.



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