Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells

Absence of functional presenilin 1 (PS1) protein leads to loss of gamma -se cretase cleavage of the amyloid precursor protein (beta APP), resulting in a dramatic reduction in amyloid beta peptide (A beta) production and accumu lation of alpha- or beta -secretase-cleaved COOH-terminal fragments of PAPP (alpha- or beta -CTFs). The major COOH-terminal fragment (CTF) in brain wa s identified as PAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily A beta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but n ot late endosomes. There were some subtle differences in the subcellular di stribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant f ibroblasts. However, there was no obvious redistribution of full-length bet a APP or of markers of other organelles in either mutant. Blockade of endop lasmic reticulum-to-Golgi trafficking indicated that in PS1-/- neurons las in normal cells) trafficking of beta APP to the Golgi compartment is necess ary before alpha- and beta -secretase cleavages occur. Thus, although we ca nnot exclude a specific role for PS1 in trafficking of CTFs, these data arg ue against a major role in general protein trafficking. These results are m ore compatible with a role for PS1 either as the actual gamma -secretase ca talytic activity or in other functions indirectly related to gamma -secreta se catalysis (e,g. an activator of gamma -secretase, a substrate adaptor fo r gamma -secretase, or delivery of gamma -secretase to beta APP-containing compartments).