Spinal cord Tau pathology induces tactile deficits and cognitive impairment in Alzheimer's disease via dysregulation of CCK neurons

Abstract

Somatosensory processing has been shown to be correlated with brain development and cognitive function, but whether and how tactile sensory deficits affect cognition decline remains unclear. Here we show that tactile function is impaired in individuals with Alzheimer's disease (AD), and this impairment is inversely correlated with Montreal Cognitive Assessment scores and positively correlated with Tau pathology. We observed similar deficits in presymptomatic 3×Tg AD mice and find that cholecystokinin (CCK)-expressing neurons in the spinal cord are highly vulnerable to Tau pathology. Expressing mutant Tau-P301S in spinal cord CCK-expressing neurons aberrantly activates the transcription factor c-Maf, inhibits CCK neurons and induces tactile deficits, whereas silencing Tau or c-Maf restores tactile sensation and improves cognition in AD model mice. Together, these gain- and loss-of-function studies demonstrate that Tau pathology in spinal cord CCK neurons contributes to tactile dysfunction and cognitive function. Targeting tactile sensation may be a promising strategy for predicting the progression of cognitive impairment in AD.