Abstract
INTRODUCTION: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood. METHODS: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology. RESULTS: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types. DISCUSSION: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential.