β‐ but not γ‐secretase proteolysis of APP causes s

Authors: Robert Tamayev Shuji Matsuda Ottavio Arancio Luciano DAdamio

Publish Date: 2012/03/08

Volume: 4, Issue: 3, Pages: 171-179

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Abstract

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia FDD BRI2 deficiency of FDD provokes an increase in amyloid‐β precursor protein APP processing since BRI2 is an inhibitor of APP proteolysis and APP mediates the synaptic/memory deficits in FDD APP processing is linked to Alzheimer disease AD pathogenesis which is consistent with a common mechanism involving toxic APP metabolites in both dementias We show that inhibition of APP cleavage by β‐secretase rescues synaptic/memory deficits in a mouse model of FDD β‐cleavage of APP yields amino‐terminal‐soluble APPβ sAPPβ and β‐carboxyl‐terminal fragments β‐CTF Processing of β‐CTF by γ‐secretase releases amyloid‐β Aβ which is assumed to cause AD However inhibition of γ‐secretase did not ameliorate synaptic/memory deficits of FDD mice These results suggest that sAPPβ and/or β‐CTF rather than Aβ are the toxic species causing dementia and indicate that reducing β‐cleavage of APP is an appropriate therapeutic approach to treating human dementias Our data and the failures of anti‐Aβ therapies in humans advise against targeting γ‐secretase cleavage of APP and/or AβMouse models are critical to explore pathogenesis and therapy of human diseases Inadequate models are a major handicap for understanding disease mechanisms and for developing disease‐modifying agents The animal models used to study Alzheimers disease are designed on the assumption that amyloid‐β Aβ plaques cause dementia Amyloid Cascade Hypothesis These models consist of transgenic mice over‐expressing mutant forms of genes causing human dementia because over‐expression is required to develop amyloid lesions in mice These mice however do not reflect the genotypes of human diseases and it is dubious whether they recapitulate the physiopathology of dementia Indeed over‐expression of human disease genes could produce artefactual harmful effects leading to erroneous information concerning the pathogenesis and therapy of dementiaTo avoid many potential artefacts of the over expression models we have produced a mouse model of human dementia genetically congruous to the human case These mice develop memory and synaptic plasticity deficits that are dependent on Aβ precursor protein APP APP is cleaved by β‐secretase which produces two APP‐metabolites called sAPPβ and β‐CTF β‐CTF is than processed by γ‐secretases to produce Aβ We show here that synaptic plasticity and memory deficits are mediated through production of sAPPβ and/or β‐CTF but not Aβ during LTP and memory acquisition The inference that Aβ may not cause synaptic and memory dysfunction is at odds with the belief that Aβ is the primary mediator of AD‐related dementias Moreover we develop a biologic compound modulator of β‐cleavage of APP MoBA that blocks β‐cleavage of APP but not β‐secretase Since β‐secretase has important biological functions the use of a β‐secretase inhibitor may produce adverse toxic effects which would be avoided using compounds with a MoBA‐like activity

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