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(Journal Article) |
Alzheimers & Dementia 7 (4) (2011)
Aβ inhibits specific kinesin motors involved in both mitosis and neuronal function; potential implications for neurogenesis and neuroplasticity in Alzheimer's disease and Down syndrome
H Potter
,
S Borysov
,
C Ari
,
A Granic
,
J Wu
ABSTRACT
Background Microtubules are highways along which ATP driven motor proteins transport key cellular components such as proteins, vesicles, chromosomes, and large macromolecules, including microtubules themselves. Many neurodegenerative diseases show defects in the microtubule transport system, underlining its importance in normal physiology. For example, microtubule dysfunction is implicated in the neurotoxicity and defective neuronal plasticity induced by the Alzheimer A08 peptide. Furthermore, we found previously that mutant amyloid precursor protein and presenilin genes and their product A08 induce chromosome mis-segregation and aneuploidy in AD patients, Tg mice, and cultured cells, processes requiring microtubule function. Confirmatory results from other labs showed that 30% of neurons in early AD cortex are aneuploid/hyperdiploid. Methods We used Xenopus egg extracts, cultured cells, and kinetic experiments with recombinant proteins to determine the effect of A08 on kinesin motors involved in mitosis. Cultured neurons, Tg AD mouse brains, and hippocampal slices were used to test that ability of A08 to inhibit one such motor in neurons. Results The data support a unifying hypothesis that A08-induced pathologies in AD result in part from A08 inhibiting specific microtubule motors. A08 added to human cells or Xenopus egg extracts impairs the formation and stability of mitotic spindles by directly inhibi