LIGHT AND ELECTRON-MICROSCOPIC LOCALIZATION OF PRESENILIN-1 IN PRIMATE BRAIN

Several genes have been implicated in the pathogenesis of early-onset familiar Alzheimer's disease. A majority of the autosomal dominant cas es are linked to recently identified mutations in the presenilin-1 gen e on chromosome 14, The native presenilin-1 protein in primates has no t been well characterized, and its precise localization is unknown. We have studied the native presenilin-1 protein in monkey brain and peri pheral tissues by using a monoclonal antibody specific for the N-termi nal domain of human presenilin-1. Western blots detect polypeptide spe cies of similar to 49 and similar to 32 kDa from COS-7 and PC12 cells transfected with full-length human presenilin-1 cDNA and from in vitro translations of the normal human presenilin-1 mRNA. A 32 kDa polypept ide is detected in monkey peripheral tissues, with the highest express ion in testis and lung. In all brain regions the 32 kDa band is the pr edominant form of presenilin-1, and it is found in particulate subfrac tions. Light microscopic immunocytochemistry reveals presenilin-1 stai ning in all brain regions, with the strongest labeling in neurons and neuropil. In addition, weaker immunoreactivity is also present in glia and blood vessels. Neuronal staining shows significant variability, w ith particularly intense labeling of certain cell types, including lar ge neocortical and hippocampal pyramidal neurons, magnocellular basal forebrain neurons, brainstem motoneurons, and some populations of inte rneurons, By electron microscopic immunocytochemistry, highly selectiv e presenilin-1 staining is seen on the cytoplasmic surfaces of membran ous organelles, which suggest localization to the endoplasmic reticulu m-Golgi intermediate compartment, a subdomain of the endoplasmic retic ulum, and some coated transport vesicles.