p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (A?) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. ...
However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of A?. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both A? and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of A? and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of A? and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.
Mesh Terms:
Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Cerebral Cortex, Disease Models, Animal, Endosomes, Mice, Knockout, Neurons, Primary Cell Culture, Receptors, Nerve Growth Factor, Signal Transduction
J Neurochem
Date: Dec. 01, 2017
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