Mutations in the COPI coatomer subunit α-COP induce release of Aβ-42 and amyloid precursor protein intracellular domain and increase tau oligomerization and release.
Understanding the cellular processes that lead to Alzheimer's disease (AD) is critical, and one key lies in the genetics of families with histories of AD. Mutations a complex known as COPI were found in families with AD. The COPI complex is involved in protein processing and trafficking. Intriguingly, several recent publications have found components of the COPI complex can affect the metabolism of pathogenic AD proteins. We reduced levels of the COPI subunit α-COP, altering maturation and cleavage of amyloid precursor protein (APP), resulting in decreased release of Aβ-42 and decreased accumulation of the AICD. Depletion of α-COP reduced uptake of proteopathic Tau seeds and reduces intracellular Tau self-association. Expression of AD-associated mutant α-COP altered APP processing, resulting in increased release of Aβ-42 and increased intracellular Tau aggregation and release of Tau oligomers. These results show that COPI coatomer function modulates processing of both APP and Tau, and expression of AD-associated α-COP confers a toxic gain of function, resulting in potentially pathogenic changes in both APP and Tau.
['Astroski|Jacob W|JW|', 'Akporyoe|Leonora K|LK|', 'Androphy|Elliot J|EJ|', 'Custer|Sara K|SK|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D000818:Animals D002478:Cells, Cultured D020755:Coat Protein Complex I D020756:Coatomer Protein D051379:Mice D009154:Mutation D010446:Peptide Fragments D016875:tau Proteins
COPI coatomer Amyloid precursor protein Tau Golgi apparatus