Wong, L.-W. | Search bioRxiv

bioRxiv2026

Primate Hippocampus Reveals Distinct Rules for Associative Synaptic Plasticity

Long-term potentiation (LTP) is a key cellular mechanism underlying learning and memory, but its conservation across species remains unclear. Using nonhuman primates (NHPs), we examined hippocampal synaptic plasticity at Schaffer collateral- CA1 synapses. Theta-burst stimulation (TBS) reliably induced LTP in NHPs, comparable to rodents. However, unlike rodents, TBS in NHPs readily engaged synaptic tagging and capture (STC), indicating a lower threshold for associative plasticity. This was accompanied by increased expression of plasticity-related proteins, including PKM{zeta} and BDNF, suggesting enhanced recruitment of protein synthesisdependent stabilization mechanisms. These findings reveal a species-specific divergence in the molecular regulation of persistent synaptic plasticity and identify an evolutionary specialization in mechanisms supporting associative memory. Together, our results highlight limitations of rodent models in fully capturing human-relevant memory processes and underscore the importance of primate systems for translational neuroscience.

neuroscience↗

bioRxiv2020

Inactive variants of death receptor p75NTR reduce Alzheimer's neuropathology by interfering with APP internalization

A prevalent model of Alzheimers disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. However, the molecular pathways that regulate APP internalization and intracellular trafficking in neurons are unknown. Here we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of A{beta} 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 p75NTR interacts with APP and regulates its internalization in hippocampal neurons. Inactive p75NTR variants internalized much slower and to lower levels than wild type p75NTR, favoring non-amyloidogenic APP cleavage by reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

neuroscience↗