The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

Abstract

Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.

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.…”

GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein

“…The microtubular cytoskeleton has already been identified as a target for therapy in neurodegenerative diseases; 39,40 here, we propose that drugs acting on the actin cytoskeleton have potential use in the treatment of PD. In addition, as depletion of the medium from Syn was sufficient to reduce the propagation of cytoskeletal pathology, the reduction of the circulating levels of Syn might be an additional therapeutic target at early stage of the disease, as suggested and reviewed in.…”

“…Denatured and non denatured Syns affected the morphology of actin cytoskeleton in a similar way, inducing both a significant increase in actin protrusion areas and resistance to depolymerization (Figures 2a and b). To exclude the possibility that the effect of Syn was due to fibril formation, we used three distinct Syn peptides: P34 (aa [34][35][36][37][38][39][40][41][42][43][44][45], that is, the glycosphingolipid-binding domain of Syn, P61 (aa 61-78), that is, the cholesterol-binding domain of Syn that has been shown to aggregate 20,21 and P12 (aa 12-23), a peptide with no recognized function. None of these peptides determined measurable effects on cytoskeleton stabilization, suggesting that the whole protein, monomeric and unfolded, is required for its action on microfilaments (Figures 2a and b).…”

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…BMS-241027 showed its functions of reversing behavioral and cognitive deficiencies and restraining neuron loss in mouse models [98,99]. A Phase 1 trial to evaluate the tolerability and pharmacology of BMS-241027 was completed in 2013, but no consequences have been demonstrated [100].…”