Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin-1 mutations

Two (P117L; M146L) familial Alzheimer's disease (FAD)-causing presenilin-1 (PS1) mutations have been tested for their effect in stably transfected mou se neuroblastoma (N2a) cell lines. The P117L mutation is associated with th e earliest onset of AD reported so far (24 years), while the M146L is less pathogenic with the onset at about 43 years. Overexpression of wild-type (w t) PS1 gene was associated with the marked increase in the number and the l ength of neuritic outgrowths accompanied by accumulation of PS1 immunoreact ivity in neurites. The highly pathogenic P117L mutation completely suppress ed this effect and the pattern of PS1 immunolabeling resembled a cup struct ure with all immunoreactivity gathered at one pole of the cell. The effect of less pathogenic M146L mutation was similar, but not as pronounced. These findings suggest that one of the normal functions of PS1 may be the contro l of neurite outgrowth, and the inhibitory effect of two FAD-linked mutatio ns stresses its importance in the cellular mechanism that leads to the deve lopment of Alzheimer's disease (AD). (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.