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Titolo:
Presenilin-1 mutations reduce cytoskeletal association, deregulate neuritegrowth, and potentiate neuronal dystrophy and tau phosphorylation
Autore:
Pigino, G; Pelsman, A; Mori, H; Busciglio, J;
Indirizzi:
Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA Univ Connecticut Farmington CT USA 06030 urosci, Farmington, CT 06030 USA Osaka City Univ, Sch Med, Dept Neurosci, Osaka 5658585, Japan Osaka City Univ Osaka Japan 5658585 Dept Neurosci, Osaka 5658585, Japan
Titolo Testata:
JOURNAL OF NEUROSCIENCE
fascicolo: 3, volume: 21, anno: 2001,
pagine: 834 - 842
SICI:
0270-6474(20010201)21:3<834:PMRCAD>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
FAMILIAL ALZHEIMERS-DISEASE; BETA-AMYLOID NEUROTOXICITY; HIPPOCAMPAL-NEURONS; MUTANT PRESENILIN-1; IN-VIVO; PROTEOLYTIC FRAGMENTS; INTRACELLULAR DOMAIN; PRECURSOR PROTEIN; TRANSGENIC MICE; NUCLEAR ACCESS;
Keywords:
Alzheimer's disease; presenilin; cytoskeleton; Notch1; amyloid beta; tau; neuronal dystrophy;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
69
Recensione:
Indirizzi per estratti:
Indirizzo: Busciglio, J Univ Connecticut, Ctr Hlth, Dept Neurosci, 263 Farmington Ave, Farmington,CT 06030 USA Univ Connecticut 263 Farmington Ave Farmington CTUSA 06030 A
Citazione:
G. Pigino et al., "Presenilin-1 mutations reduce cytoskeletal association, deregulate neuritegrowth, and potentiate neuronal dystrophy and tau phosphorylation", J NEUROSC, 21(3), 2001, pp. 834-842

Abstract

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 cytoskeletalassociation 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 22:25:13