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


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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Available from: Luciano D'adamio, Oct 13, 2015
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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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    ABSTRACT: Background Recent research in Alzheimer’s disease (AD) field has been focused on the potential role of the amyloid-β protein that is derived from the transmembrane amyloid precursor protein (APP) in directly mediating cognitive impairment in AD. Transgenic mouse models overexpressing APP develop robust AD-like amyloid pathology in the brain and show various levels of cognitive decline. In the present study, we examined the cognition of the BRI2-Aβ transgenic mouse model in which secreted extracellular Aβ1-40, Aβ1-42 or both Aβ1-40/Aβ1-42 peptides are generated from the BRI-Aβ fusion proteins encoded by the transgenes. BRI2-Aβ mice produce high levels of Aβ peptides and BRI2-Aβ1-42 mice develop amyloid pathology that is similar to the pathology observed in mutant human APP transgenic models. Results Using established behavioral tests that reveal deficits in APP transgenic models, BRI2-Aβ1-42 mice showed completely intact cognitive performance at ages both pre and post amyloid plaque formation. BRI2-Aβ mice producing Aβ1-40 or both peptides were also cognitively intact. Conclusions These data indicate that high levels of Aβ1-40 or Aβ1-42, or both produced in the absence of APP overexpression do not reproduce memory deficits observed in APP transgenic mouse models. This outcome is supportive of recent data suggesting that APP processing derivatives or the overexpression of full length APP may contribute to cognitive decline in APP transgenic mouse models. Alternatively, Aβ aggregates may impact cognition by a mechanism that is not fully recapitulated in these BRI2-Aβ mouse models.
    Molecular Neurodegeneration 05/2013; 8(1):15. DOI:10.1186/1750-1326-8-15 · 6.56 Impact Factor
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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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    ABSTRACT: Mutations in ß and genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDD, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr of ß-CTF because phosphorylation of Thr is increased in AD cases. We created a knock-in mouse bearing a ThrAla mutation ( mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDD mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr is a viable therapeutic strategy for human dementias.
    PLoS ONE 02/2013; 8(2):e57120. DOI:10.1371/journal.pone.0057120 · 3.23 Impact Factor
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    • "(See legend on next page.) Tamayev et al. Molecular Neurodegeneration 2012, 7:60 Page 6 of 11 disulfide linkage. This releases the peptide cargo and allows it to act at its target. We have previously shown that Pen1-XBIR3 inhibits caspase-9 dependent cell death using primary hippocampal neuron cultures, and that Pen1-XBIR3 delivery to the CNS blocks casp"
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    ABSTRACT: Background Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis. Results Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDDKI, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDDKI mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits. Conclusion These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias.
    Molecular Neurodegeneration 12/2012; 7(1):60. DOI:10.1186/1750-1326-7-60 · 6.56 Impact Factor
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