A?43-producing PS1 FAD mutants cause altered substrate interactions and respond to ?-secretase modulation

ABSTRACT: Abnormal generation of neurotoxic amyloid-? peptide (A?) 42/43 species due to mutations in the catalytic presenilin 1 (PS1) subunit of ?-secretase is the major cause of familial Alzheimer´s disease (FAD). Deeper mechanistic insight on the generation of A?43 is still lacking and it is unclear whether ?-secretase modulators (GSMs) can reduce the levels of this A? species. By comparing several types of A?43-generating FAD mutants, we observe that very high levels of A?43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of A?, are found for all mutants and are independent of their particular effect on A? production. Furthermore, unlike previously described GSMs, the novel compound RO7019009 can effectively lower A?43 production of all

SUBMITTER: Dr. Harald Steiner 

PROVIDER: S-SCDT-EMBOR-2019-47996V1 | biostudies-other |

REPOSITORIES: biostudies-other