Wk. Dowjat et al., Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin-1 mutations, NEUROSCI L, 267(2), 1999, pp. 141-144
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.
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