Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation

Mutations in presenilin genes are linked to early onset familial Alzheimer's disease (FAD). Previous work in non-neuronal cells indicates that presenilin-1 (PS1) associates with cytoskeletal elements and that it facilitates Notch1 signaling. Because Notch1 participates in the control of neurite growth, cultured hippocampal neurons were used to investigate the cytoskeletal association of PS1 and its potential role during neuronal development. We found that PS1 associates with microtubules (MT) and microfilaments (MF) and that its cytoskeletal association increases dramatically during neuronal development. PS1 was detected associated with MT in the central region of neuronal growth cones and with MF in MF-rich areas extending into filopodia and lamellipodia. In differentiated neurons, PS1 mutations reduced the interaction of PS1 with cytoskeletal elements, diminished the nuclear translocation of the Notch1 intracellular domain (NICD), and promoted a marked increase in total neurite length. In developing neurons, PS1 overexpression increased the nuclear translocation of NICD and inhibited neurite growth, whereas PS1 mutations M146V, I143T, and deletion of exon 9 (D9) did not facilitate NICD nuclear translocation and had no effect on neurite growth. In cultures that were treated with amyloid beta (A beta), PS1 mutations significantly increased neuritic dystrophy and AD-like changes in tau such as hyperphosphorylation, release from MT, and increased tau protein levels. We conclude that PS1 participates in the regulation of neurite growth and stabilization in both developing and differentiated neurons. In the Alzheimer's brain PS1 mutations may promote neuritic dystrophy and tangle formation by interfering with Notch1 signaling and enhancing pathological changes in tau.