β-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents

Abstract

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 A␤ [25][26][27][28][29][30][31][32][33][34][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 A␤ 1-42 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.

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

“…We note that our finding that short exposures to Ab can induce MT stability in neurons challenges the current interpretation that a primary activity of Ab is to cause MT destabilization through tau hyperphosphorylation (Michaelis et al, 1998) Michaelis et al, 2005;Zempel et al, 2010;Zhang et al, 2012). We believe that our data, although surprising, are not in contradiction with the current model but rather suggest an original interpretation that deserves further testing, that is that progressive MT destabilization upon exposure to Ab might be a consequence of the cellular response to counteract a chronic induction in the levels of stable Glu MTs.…”

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

“…Paclitaxel also blocks Aβ-induced phosphorylation of tau by preventing the cleavage of p35 by calpain (Li et al 2003). Nanomolar concentrations of paclitaxel can protect neurons against various toxic insults and enhance survival by maintaining Ca 2+ homeostasis (Burke et al 1994;Furukawa and Mattson 1995;Furukawa et al 2003;Sponne et al 2003;Michaelis et al 2005) without evidence of toxicity (Trushina et al 2003). Our study demonstrates that tau is not phosphorylated by MTstabilizing/destabilizing drugs at lower doses, but it is phosphorylated at higher doses.…”

TCP-FA4: A derivative of tranylcypromine showing improved blood–brain permeability

“…We used Aβ [25][26][27][28][29][30][31][32][33][34][35] at a concentration of 10 μM in the present studies based on earlier results. In previous studies we have shown that at this concentration we see Aβ induced loss of cortical cells by approximately 50% [20]. This level thus enables us to test drug effects that would not be possible if high Aβ concentration were used to destroy all cells.…”