Presenilin-1 mutations reduce cytoskeletal association, deregulate neuritegrowth, 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 preseni lin-1 (PS1) associates with cytoskeletal elements and that it facilitates N otch1 signaling. Because Notch1 participates in the control of neurite grow th, cultured hippocampal neurons were used to investigate the cytoskeletal association of PS1 and its potential role during neuronal development. We f ound that PS1 associates with microtubules (MT) and microfilaments (MF) and that its cytoskeletal association increases dramatically during neuronal d evelopment. PS1 was detected associated with MT in the central region of ne uronal growth cones and with MF in MF-rich areas extending into filopodia a nd lamellipodia. In differentiated neurons, PS1 mutations reduced the inter action of PS1 with cytoskeletal elements, diminished the nuclear translocat ion of the Notch1 intracellular domain (NICD), and promoted a marked increa se in total neurite length. In developing neurons, PS1 overexpression incre ased the nuclear translocation of NICD and inhibited neurite growth, wherea s PS1 mutations M146V, I143T, and deletion of exon 9 (D9) did not facilitat e NICD nuclear translocation and had no effect on neurite growth. In cultur es that were treated with amyloid beta (A beta), PS1 mutations significantl y increased neuritic dystrophy and AD-like changes in tau such as hyperphos phorylation, release from MT, and increased tau protein levels. We conclude that PS1 participates in the regulation of neurite growth and stabilizatio n in both developing and differentiated neurons. In the Alzheimer's brain P S1 mutations may promote neuritic dystrophy and tangle formation by interfe ring with Notch1 signaling and enhancing pathological changes in tau.