Abstract
γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.
Highlights
Alzheimer’s disease (AD) is characterized by cognitive deficits and is one of the most commonly diagnosed types of dementia
Notch function in the adult central nervous system (CNS) is highly restricted to the population of neural stem cells and probably other substrates could better explain the worsening of the cognitive function seen in the clinical trial
It regulates axonal growth and synaptic plasticity, as well as cell proliferation, migration, and survival (Kraemer et al, 2014; Vilar, 2017). These functions can be elicited by the association of p75 neurotrophin receptor (p75NTR) with different ligands and co-receptors leading to the activation of various signaling pathways (Roux & Barker, 2002)
Summary
Alzheimer’s disease (AD) is characterized by cognitive deficits and is one of the most commonly diagnosed types of dementia. The main reason of such failure likely relies on the fact that γ-secretases do process APP and cleave many other type 1 transmembrane proteins (De Strooper & Chavez Gutierrez, 2015), and the concomitant GSI-mediated inhibition of the cleavage of other substrates of γ-secretase likely caused the observed undesirable consequences. The p75 neurotrophin receptor (p75NTR) is a member of the TNF receptor superfamily (Ibañez & Simi, 2012; Bothwell, 2014), and it is best known by its role in programmed neuronal death during development or in response to injury in the adult brain (Ibañez & Simi, 2012) It regulates axonal growth and synaptic plasticity, as well as cell proliferation, migration, and survival (Kraemer et al, 2014; Vilar, 2017). Our results reveal a novel mechanism underlying the RIP of p75, where the oligomerization of the receptor (substrate) and its subcellular location protects it from γ-secretase–mediated processing and exacerbates its deadly function
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