<p>Although protein palmitoylation has been associated with Alzheimer’s Disease (AD), it remains unclear whether or how palmitoylation of specific proteins contributes to any of the pathological features of AD. The p75 neurotrophin receptor (p75^NTR) contributes to AD progression by regulating the intracellular trafficking and amyloidogenic processing of amyloid precursor protein (APP). p75^NTR is palmitoylated at a juxtamembrane cysteine but it is currently unknown whether this has any effect on its role in AD. Here, we report that 5xFAD mice, an animal model of AD, expressing a palmitoylation-deficient mutant of p75^NTR (p75^C281A) display significantly attenuated neuropathology and cognitive deficits. Mechanistically, p75^C281A showed enhanced internalization, trafficking to Rab5/Rab7 endosomes and lysosomal-mediated degradation. In mutant p75^C281A neurons, APP displayed accelerated co-internalization with p75^NTR, increased trafficking to late endosomes and lysosome, and enhanced degradation, thereby limiting neuronal Aβ production. Interestingly, the brain of 5xFAD mice shows increased levels of p75^NTR palmitoylation. These results indicate that palmitoylation of p75^NTR enhances its stability and, indirectly, that of APP by reducing their trafficking to the lysosome, resulting in increased Aβ accumulation and neuropathology in the AD brain. Selective inhibitors of p75^NTR palmitoylation may find applications in the treatment of AD.</p>