AD is characterized by amyloid deposition of Aβ peptides that derive from sequential cleavage of APP by β- and γ-secretases [1, 2]. Mutations in APP cause familial AD (FAD) . Familial dementia is also caused by mutations in genes that regulate APP processing. These include the PSEN1/2 genes, which code for the catalytic component of the γ-secretase, and the BRI2/ITM2b gene, whose protein product BRI2 binds APP and inhibits APP processing [3–10]. Although the familial cases caused by APP/PSEN mutations are classified as FAD and those caused by mutations in BRI2/ITM2b as Familial Danish or British dementias (FDD or FBD), recent evidence suggest that FBD and FDD share with FAD a pathogenic mechanism involving synaptic-toxic APP metabolites released during memory acquisition [11–16].
The prevailing pathogenic model for these dementias, the amyloid cascade hypothesis, posits that amyloid peptides, in forms of either amyloid plaques or oligomers, trigger dementia. In the case of AD, the amyloid peptide is Aβ, which is a part of APP and is also present in normal individuals; in the case of FDD and FBD the amyloidogenic peptides, called ADan and ABri respectively, are generated from the mutant BRI2 proteins [4, 10] and are not present in normal individuals. Notably, the FDD amyloid plaques contain both Aβ and ADan. Based on the amyloid cascade hypothesis , transgenic mice carrying mutant APP
PSEN1/2 or BRI2/ITM2b are used to model these dementias, as over-expression is necessary to reproduce amyloidosis . However, over-expression of mutant genes produce harmful effects unrelated to AD leading to erroneous information concerning pathogenesis and therapy of human diseases.
To avoid artifacts of over-expression, we generated a knock-in mouse model of FDD (FDDKI) that, like FDD patients , carries a wild type Bri2/Itm2b allele and the other with the Danish mutation . FDDKI mice develop progressive synaptic and memory deficits due to loss of Bri2, but do not develop amyloidosis . BRI2 binds to APP and inhibits cleavage of APP by secretases [6–9]. Owing to the loss of BRI2, processing of APP is increased in FDD [11, 12]. Remarkably, memory and synaptic deficits of FDDKI mice require APP , and more specifically processing of APP by β-secretase during synaptic plasticity and memory acquisition [15, 16]. The two products of β-processing of APP are sAPPβ and β-CTF. The latter is processed by γ-secretase to yield Aβ. Contrary to the amyloid hypothesis of AD pathogenesis, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDDKI mice [15, 16]. Overall, these results provide genetic evidence that APP and BRI2 functionally interact and that APP mediates FDD neuropathology, and suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia. Here, we have evaluated further the role of γ-secretase in the pathogenesis of memory deficits of FDDKI mice.