β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.
Bottom Line: 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.Show MeSH
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Mentions: We next tested the role of APP processing in the aging-dependent memory deficits of FDDKI mice (Tamayev et al, 2010b). A cannula was surgically implanted in the lateral ventricle of a cohort of 8-month-old FDDKI mice and WT littermates. Five weeks after surgery, we analysed the effect of β-secretase-inhibitor IV, MoBA and GSI on the memory deficits of FDDKI mice in a longitudinal study. Memory was analysed using novel object recognition (NOR), a non-aversive memory test that relies on the mouse's natural exploratory behaviour. Before the NOR tests, open field studies showed that FDDKI mice have no defects in habituation, sedation, risk assessment and anxiety-like behaviour in novel environments, as previously reported (Tamayev et al, 2010b). The first NOR study showed that during training, FDDKI and WT mice spent the same amount of time exploring two identical objects (Fig 4A). The following day, one of the two old objects was replaced with a new one to test the mouse's memory. WT mice preferentially explored the novel object; conversely FDDKI mice spent the same amount of time exploring the two objects as if they were both novel to them, showing that they had no memory of the objects from the previous day (Fig 4B). Two weeks later, we tested the effect of β-secretase-inhibitor IV. The mice were injected in the lateral ventricle with 1 µl of a 100 µM solution of β-secretase-inhibitor IV in PBS 1 h before the training/testing trials. Treated FDDKI mice spent significantly more time exploring the novel object just as β-secretase-inhibitor IV-treated controls (Fig 4B). Following 1 day of rest, a new NOR test performed without treatments showed that FDDKI mice had relapsed into amnesia (Fig 4B), demonstrating that the therapeutic effect of β-secretase inhibition is reversible and short-lived. Four days later, we analysed the behavioural outcome of γ-secretase inhibition. Mice were injected 1 h before the training/testing with 1 µl of a 300 nM solution of compound-E in PBS, The GSI neither improved memory of FDDKI mice nor altered performance of WT animals (Fig 4B). Two days later, we assessed the therapeutic potential of MoBA by injecting in the lateral ventricle 1 µl of a 100 µM solution of MoBA in PBS 1 h before the training/testing sections. MoBA significantly improved memory in FDDKI mice. Like for β-secretase-inhibitor IV, the therapeutic effect of MoBA was transitory. In fact, when this cohort of mice was retested after 48 h of rest and without treatments, we found that FDDKI mice had reverted to a memory-loss phenotype (Fig 4B). To exclude that compound-E was ineffective due to low-dosage, mice were rested for 1 day and retested injecting 1 µl of a 3 µM solution of compound-E in PBS 1 h before the training/testing tasks. Even this 10-fold higher GSI dose did not correct the memory deficit of Danish mice, and GSI-treated WT mice showed a trend, though not statistically significant, towards memory impairment (Fig 4B). Thus, consistent with the LTP data, β-secretase-inhibitor IV and MoBA rescued, albeit temporarily, the memory deficit of FDDKI mice, while the GSI did not.
Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.