Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

Abstract

Genetic, biochemical, and anatomical grounds led to the proposal of the amyloid cascade hypothesis centered on the accumulation of amyloid beta peptides (Aβ) to explain Alzheimer's disease (AD) etiology. In this context, a bulk of efforts have aimed at developing therapeutic strategies seeking to reduce Aβ levels, either by blocking its production (γ- and β-secretase inhibitors) or by neutralizing it once formed (Aβ-directed immunotherapies). However, so far the vast majority of, if not all, clinical trials based on these strategies have failed, since they have not been able to restore cognitive function in AD patients, and even in many cases, they have worsened the clinical picture. We here propose that AD could be more complex than a simple Aβ-linked pathology and discuss the possibility that a way to reconcile undoubted genetic evidences linking processing of APP to AD and a consistent failure of Aβ-based clinical trials could be to envision the pathological contribution of the direct precursor of Aβ, the β-secretase-derived C-terminal fragment of APP, βCTF, also referred to as C99. In this review, we summarize scientific evidences pointing to C99 as an early contributor to AD and postulate that γ-secretase should be considered as not only an Aβ-generating protease, but also a beneficial C99-inactivating enzyme. In that sense, we discuss the limitations of molecules targeting γ-secretase and propose alternative strategies seeking to reduce C99 levels by other means and notably by enhancing its lysosomal degradation.

IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization

“…Upon β-secretase-mediated (BACE1) cleavage of the β C-terminal fragment (β-CTF/C99) from APP, the γ-secretase complex produces the Aβ peptides associated with AD. Importantly, β-CTF has been shown to accumulate before Aβ peptides aggregate in vivo and, therefore, it is proposed to be an early and critical factor for initiating neurodegenerative processes and cognitive decline in AD [71][72][73]. Our data demonstrate strongly reduced levels of both β-CTF/C99 and Aβ monomers in insoluble protein fractions from Ttg mice (using 6E10 antibody) supporting the beneficial outcome on plaque burden upon astrocytic IKK2/NF-κB activation.…”

BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43

“…Lastly, we show that TDP43 219 can interact with the BAG6-recruited Ub-ligase, RNF126 and is associated with RNF126-catalyzed ubiquitylation ( Figure 5 ). In support of a general function in preventing the aggregation of neurodegeneration-associated fragments, we found that BAG6 also interacts with and solubilizes the amyloidogenic Aβ peptide and the β-secretase generated C-terminal fragment of the amyloid precursor protein, βCTF, involved in AD pathology ( Pulina et al., 2020 ; Checler et al., 2021 ). Our data support a model ( Figure 6 D) whereby limited proteolysis during pathological conditions generate proteolytic fragments containing exposed hydrophobicity.…”

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

“…The physiological significance of the presented two-substrate-mechanism will be summarized around five closely related observations from different studies of changes in γ-secretase activity in Alzheimer’s disease. Development of early diagnostic methods and effective drug-design strategies depends on our ability to connect observations from different enzyme-based, cell-based, animal-based, and clinical studies of Alzheimer’s disease [3,5,7,9,10,29].…”

“…In this study, we expand some of the earlier enzyme activity studies using advanced computational methods for the analysis of the interaction between γ-secretase, β-secretase, and C99-βCTF-APP [27,28]. Specifically, we analyze proposals that pathogenic events can be attributed to the accumulation of C99-βCTF-APP and Aβ molecules of different lengths [10,11,13,29].…”