Inactive variants of death receptor p75 NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

Autor: Ajeena Ramanujan, Lik-Wei Wong, Carlos F. Ibáñez, Ket Yin Goh, Sreedharan Sajikumar, Kazuhiro Tanaka, Chenju Yi
Rok vydání: 2021
Předmět:
Endocytic cycle
Plaque
Amyloid
Hippocampus
Amyloid beta-Protein Precursor
Mice
0302 clinical medicine
Amyloid precursor protein
Internalization
ComputingMilieux_MISCELLANEOUS
media_common
Cerebral Cortex
Mice
Knockout
Neurons
0303 health sciences
General Neuroscience
Neurodegeneration
Articles
Receptors
Death Domain
Corrigenda
Cell biology
Transmembrane domain
Protein Transport
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Amyloid
media_common.quotation_subject
ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION
Nerve Tissue Proteins
Receptors
Nerve Growth Factor
Biology
Neuroprotection
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Alzheimer Disease
mental disorders
medicine
Neurites
Animals
Humans
Molecular Biology
030304 developmental biology
Death domain
Amyloid beta-Peptides
General Immunology and Microbiology
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
HEK293 Cells
biology.protein
sense organs
Amyloid Precursor Protein Secretases
030217 neurology & neurosurgery
Zdroj: EMBO J
ISSN: 1460-2075
0261-4189
DOI: 10.15252/embj.2021109067
Popis: A prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing signaling‐deficient variants of the p75 neurotrophin receptor (p75(NTR)) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75(NTR) knock‐in mice lacking the death domain or transmembrane Cys(259) showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress, and neurite dystrophy than global knock‐outs. Strikingly, long‐term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock‐in mice. Mechanistically, we found that p75(NTR) interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75(NTR) variants internalized considerably slower than wild‐type p75(NTR) and showed increased association with the recycling pathway, thereby reducing APP internalization and co‐localization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non‐amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing, and disease progression, and suggest that inhibitors targeting the p75(NTR) transmembrane domain may be an effective therapeutic strategy in AD.
Databáze: OpenAIRE
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