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Beta-Amyloid-Induced
Neurodegeneration and Protection by
Structurally Diverse Microtubule-Stabilizing Agents |
M.
L. Michaelis, S. Ansar, Y. Chen, E. R. Reiff, K. I. Seyb, R. H. Himes, K. L. Audus,
and G. I. Georg |
-amyloid
peptide (A), hyperphosphorylation, neuronal dysfunction, cell death, Alzheimer's disease, neuronal
dystrophy |
After the final precipitation
step, neurons were suspended in fresh Dulbecco’s modified Eagle’s medium/F-12 (Sigma-Aldrich,
St. Louis, MO) with 10% fetal bovine serum (Atlanta Biologicals, Lawrenceville, GA) and plated
at a density of 2.5 x 10^5 cells in
|
Inverted
Fluorescence Microscopy |
rat |
neuronal |
cortical
cell cultures |
| |
Deposition of -amyloid peptide (A ) and hyperphosphorylation
of the protein are associated with neuronal dysfunction and cell death in Alzheimer’s disease.
Although the relationship between these two processes is not yet understood, studies have shown
that both in vitro and in vivo exposure of neurons to A leads to hyperphosphorylation and
neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel
(Taxol) protects primary neurons against toxicity induced by the A25–35 peptide. The studies
in this report were undertaken to characterize the actions of paclitaxel more fully, to assess
the effectiveness of structurally diverse microtubulestabilizing agents in protecting neurons,
and to determine the time course of the protective effects of the drugs. Primary neurons were
exposed to A in the presence or absence of several agents shown to interact with microtubules,
and neuronal survival was monitored. Paclitaxel protected neurons against A1–42 toxicity,
and paclitaxel-treated cultures exposed to A showed enhanced survival over A-only cultures
for several days. Neuronal apoptosis induced by A was blocked by paclitaxel. Other taxanes
and three structurally diverse microtubule- stabilizing compounds also significantly increased
survival of A-treated cultures. At concentrations below 100 nM, the drugs that protected the
neurons did not produce detectable toxicity when added to the cultures alone. Although multiple
mechanisms are likely to contribute to the neuronal cell death induced by oligomeric or fibrillar
forms of A, low concentrations of drugs that preserve the integrity of the cytoskeletal network
may help neurons survive the toxic cascades initiated by these peptides. |
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