NEURONAL LOCALIZATION OF PRESENILIN-1 AND ASSOCIATION WITH AMYLOID PLAQUES AND NEUROFIBRILLARY TANGLES IN ALZHEIMERS-DISEASE

Mutations in the presenilin-1 (PS1) gene is a cause of early-onset fam ilial Alzheimer's disease (AD). Endogenous PSI is associated with the endoplasmic reticulum in the cell body of undifferentiated SH-SY5Y neu roblastoma cells. At early stages of neuronal differentiation in rat h ippocampal culture, PS1 appears in all neuritic processes and in growt h cones. In mature differentiated neurons, PS1 is concentrated in the somatodendritic compartment but is also present at lower levels in axo ns. A similar localization of PS1 is observed in vivo in neurons of th e adult human cerebral cortex. In sporadic AD, PS1 appears in the dyst rophic neurites of mature amyloid plaques and colocalizes with a subse t of intraneuronal neurofibrillary tangles (NFTs). About 30% of hippoc ampal NFTs are labeled with a highly specific antibody to the PS1 C-te rminal loop domain but not with an antibody to the PS1 N terminus. Thi s observation is consistent with a potential association of the PS1 C- terminal fragment with NFTs, because PS1 is constitutively cleaved to N- and C-terminal fragments in neurons. These results suggest that PS1 is highly expressed and broadly distributed during early stages of ne uronal differentiation, consistent with a role for PS1 in neuronal dif ferentiation. Furthermore, the co-localization of PS1 with NFTs and pl aque dystrophic neurites implicates a role for PS1 in the diverse path ological manifestations of AD.