Mutations in the COPI coatomer subunit α-COP induce release of Aβ-42 and AICD and increase Tau oligomerization and release.

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, afflicting more than five million Americans; it is the 6th leading cause of death in the United States. As the population ages, the number of Americans with AD expected to increase dramatically. Understanding the cellular processes that lead to AD pathology is critical to designing meaningful therapeutic interventions. AD is characterized by the accumulation of aggregated proteins that may be toxic and may represent failure of the cell to normally process these proteins. One key to understanding sporadic AD lies in the genetics of families with highly penetrant histories of the disease. Mutations in subunits of a cellular trafficking complex known as COPI were found in families with AD and no other known AD-associated mutations. The COPI complex is involved in protein processing and trafficking within the cell. Intriguingly, several recent publications have found that components of the COPI complex can affect metabolism of pathogenic AD proteins. We report here that reducing levels of the COPI subunit α-COP alters maturation and cleavage of amyloid precursor protein (APP), resulting in decreased release of Aβ-42 and decreased accumulation of the amyloid precursor protein intracellular c-terminal domain (AICD). We also found that depletion of α-COP reduces uptake of proteopathic Tau seeds and reduces intracellular Tau self-association. Expression of AD-associated mutations in α-COP altered APP processing, resulting in increased release of Aβ-42 and increased intracellular Tau aggregation and release of Tau oligomers. Taken together, these results show that COPI coatomer function modulates the processing of both APP and Tau, and that expression of AD-associated α-COP mutant proteins confers a toxic gain of function which results in potentially pathogenic changes in both APP and Tau.