Journal
LIFE SCIENCE ALLIANCE
Volume 4, Issue 4, Pages -Publisher
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202000844
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Funding
- Generalitat Valenciana [2018-55]
- Formacion de Personal Investigador (FPI) [BFU2013/42746-P]
- Fonds voor Wetenschappelijk Onderzoek or Flanders Research Foundation (FWO) research project [G0B2519N]
- Stichting Alzheimer Onderzoek [S16013]
- [SAF2017-84096-R]
- [EEBB-I-15-10278]
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Research shows that treatment with gamma-secretase inhibitors leads to the oligomerization of p75CTF, resulting in cell death of BFCNs, possibly mediated by TrkA activity. The findings suggest that inhibiting gamma-secretase activity in older patients may accelerate cholinergic dysfunction and neurodegeneration.
gamma-secretase inhibitors (GSI) were developed to reduce the generation of A beta 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 gamma-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 gamma-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.
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