RT Journal Article SR Electronic T1 TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000844 DO 10.26508/lsa.202000844 VO 4 IS 4 A1 María Luisa Franco A1 Irmina García-Carpio A1 Raquel Comaposada-Baró A1 Juan J Escribano-Saiz A1 Lucía Chávez-Gutiérrez A1 Marçal Vilar YR 2021 UL https://www.life-science-alliance.org/content/4/4/e202000844.abstract AB 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.