Intracellular protein GBF1 displays significant associations with amyloid pathology in Alzheimer's disease.

INTRODUCTION: Despite the identification of familial Alzheimer's disease (FAD) genes and neuropathological alterations, AD displays complex genetic heterogeneity and molecular pathogenesis that warrant further investigation. GBF1 (Golgi brefeldin A resistant guanine nucleotide exchange factor 1) regulates protein trafficking, and genetic variants of GBF1 are associated with axonal neuropathy, intelligence, and cognitive function. METHODS: We sought to identify GBF1 neuropathological and molecular alterations using human post mortem brains, 5XFAD mouse brains, and FAD cells, as well as two family-based datasets (total sample size of 2522) to explore candidate GBF1 variants associated with AD. RESULTS: GBF1 revealed neuropathological alterations in association with amyloid plaques. Genetic analysis identified GBF1 suggestive variants associated with AD. Downregulation of GBF1 retarded amyloid beta (Aβ) protein precursor maturation and reduced levels of Aβ proteins. DISCUSSION: Collectively, GBF1 reveals neuropathological alterations in AD, and may lead to AD by a pathogenic mechanism altering Aβ levels and amyloid deposition in the brain.