Premium
S4‐02‐03: Tau and GSK‐3B
Author(s) -
Brion JeanPierre,
Ando Kunie,
Héraud Céline,
Leroy Karelle,
Morel Marina
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1950
Subject(s) - gsk 3 , tau protein , tauopathy , phosphorylation , microbiology and biotechnology , genetically modified mouse , gsk3b , chemistry , microtubule , transgene , biology , neuroscience , neurodegeneration , alzheimer's disease , biochemistry , medicine , disease , gene
Background: An important part of AD pathogenesis involves defects in bidirectional axonal transport driven by kinesin and dynein, and regulated by tau, along microtubules. How these defects contribute to AD is not well understood. Methods: We used semi-automated analysis of APP vesicle movement in Drosophila and mouse neurons. We also used standard reprogramming methods for fibroblasts from human AD patients. We developed new quantitative methods for generating and purifying neurons made from human embryonic stem cells and induced pluripotent stem cells, as well as methods for evaluating a range of normal and disease phenotypes in these cells. Results: In one part of my talk, I will describe our recent data implicating betaand gamma-secretase cleavage of amyloid precursor protein (APP), and Glycogen Synthase Kinase 3 (GSK-3) in the regulation of APP vesicle movement in axons. In the second part of my talk, I will describe howwe havemoved these investigations into human neurons by using human embryonic and human induced pluripotent stem cells to generate human neurons that carry the genetic changes that cause hereditary or sporadic Alzheimer’s disease to try and test these ideas. Conclusions: Our data from animal models suggest that regulation of APP movement may be key to AD pathology, but do not establish whether defects in vesicle movement are early or late in disease development in bona fide human AD neurons. Our data suggest that genomes from familial and sporadic AD patients generate early defects in purified human neurons in culture.