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

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 Cys²⁵⁹ 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.