β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.
APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias.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.
Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
- Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism*
- Amyloid beta-Peptides/genetics/metabolism*
- Cerebellar Ataxia/enzymology*/genetics/physiopathology/psychology*
- Neuronal Plasticity*
- Disease Models, Animal
- Enzyme Inhibitors/pharmacology
- Membrane Proteins/genetics/metabolism
- Mice, Knockout
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fig03: MoBA and a β-secretase inhibitor rescue the LTP deficit of FDDKI mice—a GSI does notSixty-minutes perfusion with MoBA reverses LTP impairment in FDDKI mice [WT to FDDKI: F(1,12) = 12.372, p = 0.004; WT to FDDKI + MoBA 1 µM: F(1,12) = 0.012, p = 0.914; WT to FDDKI + MoBA 10 nM: F(1,11) = 0.202, p = 0.662; FDDKI to FDDKI + MoBA 1 µM: F(1,12) = (10.078), p = 0.006; FDDKI to FDDKI + MoBA 10 nM: F(1,11) = 15.049, p = 0.008]. N6 does not rescue the LTP deficit [FDDKI to FDDKI + N6 1 µM: F(1,10) = 0.053, p = 0.821]. MoBA does not alter LTP of WT mice [WT to WT + MoBA 1 µM: F(1,12) = 0.361, p = 0.560].β-secretase-inhibitor IV (50 nM; IC50 = 15 nM) rescues LTP impairment in FDDKI mice [FDDKI to FDDKI + β-secretase-inhibitor IV: F(1,14) = 12.258, p = 0.004; WT to FDDKI: F(1,13) = 12.272, p = 0.004; WT to FDDKI + β-secretase-inhibitor IV: F(1,13) = 0.604, p = 0.451]. There was a trend towards increased LTP in inhibitor IV-treated WT and FDDKI samples versus vehicle-treated WT controls, but this difference was not statistically significant. Compound-E (1nM; IC50 = 300/240pM) does not rescue the LTP defect in FDDKI samples [FDDKI to FDDKI + compound-E: F(1,11) = 0.838, p = 0.380]. The β- and GSIs do not alter LTP of WT mice [WT to WT + β-secretase-inhibitor IV: F(1,10) = 0.413, p = 0.535; WT to WT + compound-E: F(1,11) = 0.041, p = 0.844].Lysates from hippocampal slices treated with (+) or without (−) compound-E for 3 h, were analysed by WB for APP and CTFs. The bottom graph represents quantization of triplicate samples. The CTFs levels are expressed as a % of APP.
Long-term potentiation (LTP), a synaptic plasticity phenomenon that underlies memory, is defective in the hippocampal Schaffer collateral pathway of FDDKI mice. To examine the effect of MoBA on LTP, hippocampal slices were perfused with MoBA for 60 min before inducing LTP. Both at 1 µM or 10 nM concentrations MoBA reversed the LTP deficit of FDDKI samples and did not alter LTP in WT mice (Fig 3A). N6, which does not inhibit APP processing (Fig 2A), did not rescue LTP of FDDKI mice (Fig 3A). Since perfusing hippocampal slices with a 50 nM concentration of β-secretase-inhibitor IV for 1 h before inducing LTP exhibited the same effect of MoBA (Fig 2B), it is reasonable to conclude that MoBA ameliorates LTP of FDDKI mice by inhibiting β-cleavage of APP and not by unrelated mechanisms.