Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy.
Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.
Vishruti
V
Makani
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.
Bin
B
Zhang
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Heeoon
H
Han
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.
Yuemang
Y
Yao
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.|Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Pierrik
P
Lassalas
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Kevin
K
Lou
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Ian
I
Paterson
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.
Virginia M Y
VM
Lee
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.
John Q
JQ
Trojanowski
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA.|Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Carlo
C
Ballatore
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Amos B
AB
Smith
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Maloney 3, Philadelphia, PA, 19104, USA. kbrunden@upenn.edu.
Kurt R
KR
Brunden
Alzheimer’s; Drug; Microtubule; Mouse; Pathology; Tauopathy; Transgenic
Invest New Drugs. 2007 Dec;25(6):565-70
17618407
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):227-31
15615853
Biologics. 2008 Dec;2(4):789-811
19707459
J Neurosci Res. 1997 Apr 15;48(2):128-32
9130141
Neuropathology. 2006 Oct;26(5):484-90
17080729
J Pharmacol Exp Ther. 2008 Apr;325(1):146-53
18199809
J Neuropathol Exp Neurol. 1996 Sep;55(9):964-72
8800092
Nat Rev Clin Oncol. 2010 Jan;7(1):22-36
19997076
ACS Med Chem Lett. 2013 Jul 23;4(9):886-9
24900764
J Cell Biol. 1987 Nov;105(5):2167-77
3316248
Am J Pathol. 2003 May;162(5):1623-7
12707046
Brain. 2012 Mar;135(Pt 3):807-18
22366796
J Neurol Sci. 1982 Nov;56(2-3):343-56
7175555
Nat Med. 1996 Jul;2(7):783-7
8673924
Science. 1998 Dec 4;282(5395):1914-7
9836646
Am J Surg Pathol. 2008 Mar;32(3):473-7
18300801
Nat Rev Drug Discov. 2009 Oct;8(10):783-93
19794442
Gut. 2000 Nov;47(5):632-7
11034578
Biochemistry. 1994 Aug 16;33(32):9511-22
8068626
Science. 2008 Feb 22;319(5866):1086-9
18202255
Lancet Neurol. 2014 Jul;13(7):676-85
24873720
J Neurosci. 2012 May 23;32(21):7137-45
22623658
Oncologist. 2007 Mar;12(3):271-80
17405891
Nat Rev Neurosci. 2007 Sep;8(9):663-72
17684513
Neurology. 1992 Mar;42(3 Pt 1):631-9
1549228
J Neurosci. 2010 Oct 13;30(41):13861-6
20943926
Bioorg Med Chem. 2014 Sep 15;22(18):5040-9
24433963
Curr Med Chem. 2014;21(23 ):2591-8
24533805
Biochem Soc Trans. 2012 Aug;40(4):661-6
22817712
Mol Biol Cell. 1992 Oct;3(10):1141-54
1421571
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):87-92
17190808
Nature. 1998 Jun 18;393(6686):702-5
9641683
Neurobiol Dis. 2009 May;34(2):381-8
19264130
Am J Pathol. 2013 Aug;183(2):344-51
23885714
J Neurosci. 1997 Aug 1;17 (15):5726-37
9221771
J Neurochem. 2006 Aug;98(3):973-84
16893427
J Cell Sci. 1996 Jun;109 ( Pt 6):1537-43
8799840
Neuron. 2007 Feb 1;53(3):337-51
17270732
Lab Invest. 1992 Feb;66(2):212-22
1735956
Annu Rev Neurosci. 2001;24:1121-59
11520930
J Cell Biol. 2002 Mar 18;156(6):1051-63
11901170
J Biol Chem. 2004 Nov 26;279(48):49694-703
15364924
J Neurosci. 2012 Mar 14;32(11):3601-11
22423084
Ann Neurol. 1997 Jan;41(1):17-24
9005861
Pharmacol Res. 2011 Apr;63(4):341-51
21163349