Because distinct mutations in
presenilin 1 and
presenilin 2 are a major cause of early-onset familial
Alzheimer's disease, we generated four
monoclonal antibodies for the identification, localization, and investigation of
presenilins in various cell lines and tissues from patients and controls. We show that these
antibodies are specific for the N- and C-terminal domains of human
presenilin 1 and
presenilin 2. They recognize
presenilin full-length
proteins and their approximately 28-35 kDa N-terminal fragments and approximately 18-20 kDa C-terminal fragments. None of the
antibodies showed cross-reaction in their specific detection ability. We demonstrated that
presenilin 1 and
presenilin 2 are proteolytically processed in human
glioma cell lines, transfected and untransfected human
neuroblastoma SH-SY5Y cells, COS-7 cells, rat cerebellar neuronal ST15 cells, mouse and human brain. Remarkably, we observed that
presenilin 2 is alternatively cleaved during apoptosis, producing smaller C-terminal fragments. By analyzing the subcellular distribution of
presenilins, we found reticular and fine vesicular staining throughout the cell bodies. In addition, staining of Golgi compartments and the perinuclear envelope was observed.
Alzheimer's disease brain showed strong immunoreactivity of
presenilin 1 in reactive astrocytes and
senile plaques. This high expression of
presenilin 1 may explain the increased production and accumulation of the
amyloid-beta peptide in patients with sporadic
Alzheimer's disease in the absence of familial
presenilin mutation.