TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition.
Alzheimer Disease
/ etiology
Amino Acid Motifs
Amyloid Precursor Protein Secretases
/ antagonists & inhibitors
Cell Death
/ drug effects
Cholinergic Neurons
/ drug effects
Cycloheximide
/ pharmacology
Endocytosis
Humans
Ligands
MAP Kinase Signaling System
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
/ drug effects
Proteolysis
Receptor, Nerve Growth Factor
/ chemistry
Receptor, trkA
/ metabolism
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
08
07
2020
revised:
11
01
2021
accepted:
11
01
2021
entrez:
4
2
2021
pubmed:
5
2
2021
medline:
5
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33536237
pii: 4/4/e202000844
doi: 10.26508/lsa.202000844
pmc: PMC7898468
pii:
doi:
Substances chimiques
Ligands
0
NTRK1 protein, human
0
Receptor, Nerve Growth Factor
0
Cycloheximide
98600C0908
Receptor, trkA
EC 2.7.10.1
Amyloid Precursor Protein Secretases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021 Franco et al.
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