β‐ but not γ‐secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

Abstract

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.

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

“…The adverse impact of β-CTF on synaptic plasticity and neuronal function has attracted increasing interest (35,(41)(42)(43)(44)58). In our present studies, β-CTF, but not α-CTF, had detrimental effects on neuronal function, although they only differ in the first 16 N-terminal residues (see Methods).…”

“…Additionally, the γ-secretase inhibitor (GSI) semagacestat, which eliminates all Aβ species while increasing APP-CTF levels, has shown severe adverse effect in clinical trials, which is likely associated with APP CTFs in AD patients (13,14,39,40). APP CTFs have since been shown to induce neuronal dysfunction and cognitive deficits in animal models (41)(42)(43)(44).…”

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…In fact, increases in C99 were already shown to contribute to other aspects of the pathogenesis of the disease (Saito et al , 2011; Lauritzen et al , 2012), including endosomal dysfunction (Jiang et al , 2010), hippocampal degeneration (Lauritzen et al , 2012), and altered Tau proteostasis (Moore et al , 2015). In addition, elevations in C99 are toxic to neurons (Neve et al , 1996), correlating with symptoms of the disease (Rockenstein et al , 2005; Tamayev et al , 2012). Importantly, we note that although much of our data were obtained using FAD models and cells from FAD patients containing mutations in presenilins, alterations in γ‐secretase activity and increased levels of C99 have been detected in sporadic AD patients as well (Fukumoto et al , 2002; Yang et al , 2003; Li et al , 2004; Pera et al , 2013).…”

Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer's disease

“…In fact, the overexpression of human AβPP in olfactory sensory neurons has been shown to lead to apoptosis and changes in neuronal morphology (Cheng, et al, 2013, Cheng, et al, 2011). For example, other AβPP metabolites such as AβPP-CTFs and soluble AβPP have been shown to induce neurotoxicity, cell death and resulting memory loss (Bach, et al, 2001, Bertrand, et al, 2001, Devi and Ohno, 2012, Dewachter, et al, 2002, Deyts, et al, 2012, Lu, et al, 2000, McPhie, et al, 2001, Sopher, et al, 1994, Tamayev and D’Adamio, 2012, Tamayev, et al, 2012, Yankner, et al, 1989). Our present results demonstrate high levels of AβPP-CTFs in neurons in brain regions corresponding to the olfactory pathway, with higher levels in the aPCX than in HPX, LEC, and OB, and the lowest found in the cerebellum.…”

“…Cleavage by the latter results in a β C-terminal fragment (βCTF) that contains the Aβ domain and generates Aβ and AβPP intracellular cytoplasmic domain when further processed by γ-secretase (Zheng and Koo, 2006, Zheng and Koo, 2011). The human AβPP metabolites Aβ and AβPP-CTF have been shown to exhibit some level of cytotoxicity in the pre-depositing brain, ranging from inducing endosome anomalies and apoptosis (Bertrand, et al, 2001, Cheng, et al, 2013, Deyts, et al, 2012, Jiang, et al, 2010, Kayed, et al, 2003, Lauritzen, et al, 2012, Lu, et al, 2000, McPhie, et al, 2001, Nhan, et al, 2014, Tamayev and D’Adamio, 2012, Tamayev, et al, 2012, Upadhaya, et al, 2012) to causing abnormal rewiring of neurons (Cheng, et al, 2011) and functional disruption of synapses (Lacor, et al, 2004). …”