Transsynaptic complex dysfunction in the hippocampus of Alzheimer's disease patients.Front Aging Neurosci 2026; 18:1837327.FA
INTRODUCTION
Alzheimer's disease (AD) involves not only amyloid-β and tau pathology but synaptic dysfunction and impaired autophagy, though the underlying mechanisms and their relationship to AD progression are not well understood. Transsynaptic complexes involving presynaptic neurexins (Nrxn1/2/3), secreted cerebellins (Cbln1/2/3/4), and postsynaptic glutamate delta receptors (GluD1/2) play critical roles in organizing synapses and synaptic plasticity. Studies in pain models have reported that treatment with recombinant Cbln1 rescues AMPA glutamate receptor imbalance, promotes autophagy, and inhibits hyperexcitability and pain behaviors. Here we tested the novel hypothesis that dysregulation of Cbln-GluD-based transsynaptic complexes may occur in the brain of AD patients, providing insights into disease progression and potential avenues for therapeutic development.
METHODS
We analyzed human hippocampal tissues from the TTUHSC Garrison Brain Bank and the NIH NeuroBioBank for expression of transsynaptic complex components in addition to autophagy and neuroplasticity pathways. Their expression in hippocampus was compared between control samples of Braak stages 0/1 and AD samples showing either mild (Braak stage 2) or severe (Braak stages 5/6) neurofibrillary tangle pathology. Co-immunoprecipitation was used to examine protein-protein interactions.
RESULTS
We found significantly decreased protein levels of Cbln1 and GluD2 in AD hippocampus. In the autophagy pathway, PIST and beclin-1 were decreased in AD hippocampus. Co-immunoprecipitation revealed interactions between GluD1 and PIST and between PIST and beclin-1, suggesting possible regulatory interactions between transsynaptic complex elements and autophagy in human hippocampus. We further observed decreased BDNF, consistent with diminished neuroplasticity. Finally, cofilin phosphorylation was decreased in AD, suggesting disruption of trafficking and formation of cofilin-actin rods.
DISCUSSION
These results suggest that the homeostasis of signaling molecules important for synaptic integrity is disrupted in the human hippocampus at both early- and late-stage AD. The loss of transsynaptic complex expression is accompanied by the downregulation of autophagy and neuroplasticity markers that are known to be linked to AD pathology.
