Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Abstract

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP wt ) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ 42 ) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ 42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.

Induction of Bax-dependent neuronal apoptosis by Amyloid-β Protein Precursor (AβPP) requires its localization to functional mitochondria

“…Our previous study is in agreement with others showing that full length WT AβPP can induce apoptosis in the human SH-SY5Y neuroblastoma and differentiated NBP2 neuroblastoma cell lines [17,18]. Furthermore, an in vivo study using WT AβPP overexpressing mice showed that these mice develop memory deficits independently of Aβ accumulation in the hippocampus [19]. Collectively, the above studies suggest that full length AβPP may contribute to AD pathogenesis; however, whether its localization to mitochondria is necessary to induce neuronal cell death is currently unknown.…”

“…While it has been well documented that Aβ fragments induce cell death both in vitro and in vivo, there is emerging evidence that AβPP and its intracellular domain (AICD) may also contribute to AD pathogenesis [16][17][18][19]27,28]. In this study, the overexpression of AβPP in a mouse hippocampal cell line induced a caspase-dependent and Bax-mediated apoptotic pathway which appeared to be largely independent of AβPP processing.…”

“…In this context, patients with Down Syndrome typically develop early onset AD that is most often attributed to expressing an extra copy of the AβPP gene which is localized to chromosome 21 [33][34][35][36]. The overexpression of AβPP has been shown to induce neuronal apoptosis in a variety of in vitro and in vivo models [16][17][18][19]37]. For example, Simón, et al (2009) [19] observed that the overexpression of WT AβPP in mice led to memory deficits and hippocampal neurodegeneration which were independent of Aβ accumulation.…”

“…The overexpression of AβPP has been shown to induce neuronal apoptosis in a variety of in vitro and in vivo models [16][17][18][19]37]. For example, Simón, et al (2009) [19] observed that the overexpression of WT AβPP in mice led to memory deficits and hippocampal neurodegeneration which were independent of Aβ accumulation. On the other hand, mutant AβPP expressing mice displayed high levels of Aβ in hippocampus, but Cox-IV, GAPDH and Na/K ATPase blots indicate the relative purity of the mitochondrial, cytoplasmic and plasma membrane fractions, respectively.…”

Effect of the beta secretase-1 inhibitor on the amyloid C-terminal fragment of amyloid precursor protein processing in a hyperphosphorylated tau rat model

“…A large amount of Aβ was found to be generated in cell lines of tau hyperphosphorylation, which could not be clearly explained by the amyloid cascade hypothesis (Fukumoto et al, 2002). In addition, another report showed that in mice overexpressing wild-type human amyloid precursor protein (APP), memory deficits and increasing levels of phosphorylated tau occurred early, whereas Aβ was not detected, which supported the view of an Aβ-independent pathogenic pathway in AD (Simón et al, 2009). Other studies have indicated that tau phosphorylation plays an important role in AD pathology (Oddo et al, 2006;Roberson et al, 2007).…”