Enrichment of presenilin 1 peptides in the membranes of neuronal vesicles: Implications for Alzheimer's disease

Alzheimer's disease (AD) is caused by heterogeneous genetic and probably environmental factors. Although the etiology of the disease is still not clear, several lines of evidence indicate that the integrity and number of cellular organelles that sustain neuronal vesicular axoplasmic transport, including ER, Golgi, endosomes and LDCVs are compromised in AD. These observations suggest that those factors that compromise neuronal vesicular transport may also be causally involved in the development of AD. This hypothesis, while it does not disregard the pathological significance and consequences of NFTs and NPs, emphasizes the need to search for abnormalities in neuronal protein transport upstream of the formation of NFTs and NPs. Presenilin 1 (PS1) is an integral membrane protein of unknown function. Most of this protein is cleaved post-translationally to yield an N-terminal fragment and a C-terminal fragment. Many PS1 mutants have been linked to the development of FAD. We obtained evidence that PS1 proteolytic fragments are enriched in LDCVs, CGs, and SDCCV preparations, suggesting that this protein is expressed in these vesicles and may play a role in vesicular function. These observations raise the possibility that PS1 FAD mutations interfere with the vesicular function of the PS1 fragments and cause AD, according to a model where multiple mutations of a protein induce the same disease phenotype by affecting multiple properties of the protein.