Article

β - but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
EMBO Molecular Medicine (Impact Factor: 8.67). 03/2012; 4(3):171-9. DOI: 10.1002/emmm.201100195
Source: PubMed

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 Aβ.

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    • "Diverse hypothesis were put forward to explain the disappointing results obtained by current anti-Aβ treatments. First, other APP fragments, like the β-carboxy terminal fragment (β-CTF; Lahiri et al., 2002; Pimplikar et al., 2010; Lauritzen et al., 2012; Tamayev et al., 2012; Goutagny et al., 2013), the amyloid intracellular domain (AICD), or the recently described CTF-η (Willem et al., 2015), might play key roles in AD pathogenesis and associated cognitive symptoms. A second hypothesis highlights the fact that treatments were given too late in the time-course of AD, when neuronal damages are already too extensive and irreversible. "
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    Full-text · Article · Jan 2016 · Frontiers in Cellular Neuroscience
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    • "The overexpression of full-length human APP in transgenic mice generates multiple biologically active APP proteolytic fragments, potentially capable of altering behaviour. For example, the accumulation of amino-terminal-soluble APPβ (sAPPβ) and/or β-carboxyl-terminal fragments (β-CTF) may affect long-term potentiation (LTP) [5] and memory acquisition in mouse models [6]. Thus, the relative contribution of Aβ and/or other APP metabolites to cognitive deficits in the APP over-expression models is challenging to resolve. "
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    • "Memory and synaptic deficits of FDDKI mice require APP [14], and are mediated by sAPPß and/or ß-CTF produced during synaptic plasticity and memory acquisition. Inhibition of γ-secretase, the enzyme that processes β-CTF to yield Aß, worsens memory deficits and is associated with an accumulation of ß-CTF [10], [16], [17]. In addition, caspase-9 in activated in FDDKI mice and caspase-9 activity mediates memory/synaptic plasticity deficits [18]. "
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