Primate-specific 82-kDa choline acetyltransferase attenuates progression of Alzheimer's disease-like pathology in the APPNL-G-F knock-in mouse model

Alzheimer's disease (AD) is characterized by amyloidosis, neuroinflammation, cholinergic dysfunction and cognitive impairment. In AD, the cholinergic neuronal marker choline acetyltransferase (ChAT) is reduced and the primate-specific nuclear isoform, 82-kDa ChAT, is mislocalized to cytoplasm. Cell-based studies suggest a role for 82-kDa ChAT in regulating expression of AD-related genes with potential reductions in beta-amyloid (A beta) levels. To study this further, we crossed transgenic mice expressing human 82-kDa ChAT with the AD mouse model APP(NL-G-F) and used molecular techniques and neurobehavioral tests to study the impact of 82-kDa ChAT on AD pathology. These mice had altered expression of genes linked to A beta clearance and inflammation, and reduced cognitive decline, amyloidosis and gliosis. These effects were inversely related to age and A beta plaque load and correlated best with 82-kDa ChAT localized to nuclei of neurons. The study suggests a role for 82-kDa ChAT in decreasing AD-like pathology.