Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches
Posted February 02, 2016
Presented By
Overview
Microtubule-associated protein tau helps maintain the stability and flexibility of microtubules in neuronal axons. Alternative splicing of the tau gene, MAPT, produces 6 isoforms of tau in the brain and many more in the peripheral nervous system. Tau can be phosphorylated at over 30 sites, and it undergoes many posttranslational modifications to operate as a substrate for multiple enzymes. However, tau also mediates pathological functions including neuroinflammatory response, seizure, and amyloid-β (Aβ) toxicity, and tau pathology is a hallmark of conditions including frontotemporal dementia, traumatic brain injury (TBI), Down syndrome, focal cortical dysplasia, and Alzheimer's disease (AD), as well as some tumors and infections. On September 18, 2015, speakers at the Brain Dysfunction Discussion Group's Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches symposium discussed the mechanisms by which tau becomes pathological and how the pathology spreads. They also described emerging therapeutic strategies for AD focused on tau.
How to cite this eBriefing
The New York Academy of Sciences. Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches. Academy eBriefings. 2016. Available at: www.nyas.org/Tau2015-eB
Journal Articles
Ahmed Z, Cooper J, Murray TK, et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014;127(5):667-83.
Andreadis A. Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta. 2005;1739(2-3):91-103.
Arif M, Kazim SF, Grundke-Iqbal I, et al. Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam. Proc Natl Acad Sci U S A. 2014;111(3):1144-9.
Basurto-Islas G, Grundke-Iqbal I, Tung YC, et al. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J Biol Chem. 2013;288(24):17495-507.
Bhaskar K, Konerth M, Kokiko-Cochran ON, et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19-31.
Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505-8.
Bomfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aβ oligomers. J Clin Invest. 2012;122(4):1339-53.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59.
Braak H, Rüb U, Schultz C, Del Tredici K. Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases. J Alzheimers Dis. 2006;9(3 Suppl):35-44. Review.
Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015;16(2):109-20.
Cavallini A, Brewerton S, Bell A, et al. An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease. J Biol Chem. 2013;288(32):23331-47.
Chai X, Wu S, Murray TK, et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011;286(39):34457-67.
Chien DT, Szardenings AK, Bahri S, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis. 2014;38(1):171-84.
Chiu IM, Morimoto ET, Goodarzi H, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4(2):385-401.
Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909-13.
Falcon B, Cavallini A, Angers R, et al. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2015;290(2):1049-65.
Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010;33(7):317-25.
Himmelstein DS, Ward SM, Lancia JK, et al. Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther. 2012;136(1):8-22.
Holmes BB, Diamond MI. Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target. J Biol Chem. 2014;289(29):19855-61. Review.
Holmes BB, Furman JL, Mahan TE, et al. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014;111(41):E4376-85.
King ME, Kan HM, Baas PW, et al. Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol. 2006;175(4):541-6.
Kondo A, Shahpasand K, Mannix R, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015;523(7561):431-6.
Lee S, Varvel NH, Konerth ME, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010;177(5):2549-62.
Lu KP, Zhou XZ. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol. 2007;8(11):904-16.
Marquié M, Normandin MD, Vanderburg CR, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78(5):787-800.
McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-35.
Mirbaha H, Holmes BB, Sanders DW, et al. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J Biol Chem. 2015;290(24):14893-903.
Mohamed NV, Plouffe V, Rémillard-Labrosse G, et al. Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons. Sci Rep. 2014;4:5715.
Nakamura K, Greenwood A, Binder L, et al. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell. 2012;149(1):232-44.
Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362-81.
Nussbaum JM, Schilling S, Cynis H, et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated Amyloid-β. Nature. 2012;485(7400):651-5.
Patterson KR, Remmers C, Fu Y, et al. Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease. J Biol Chem. 2011;286(26):23063-76.
Pooler AM, Polydoro M, Wegmann S, et al. Propagation of tau pathology in Alzheimer's disease: identification of novel therapeutic targets. Alzheimers Res Ther. 2013;5(5):49.
Ransohoff RM. Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity. 2009;31(5):711-21. Review.
Rapoport M, Dawson HN, Binder LI, et al. Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002;99(9):6364-9.
Roberson ED, Scearce-Levie K, Palop JJ, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007;316(5825):750-4.
Sanders DW, Kaufman SK, DeVos SL, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82(6):1271-88.
Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics. 2008;5(3):443-57. Review.
Seward ME, Swanson E, Norambuena A, et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J Cell Sci. 2013;126(Pt 5):1278-86.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280-92.
Vossel KA, Xu JC, Fomenko V, et al. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3?. J Cell Biol. 2015;209(3):419-33.
Ward SM, Himmelstein DS, Lancia JK, Binder LI. Tau oligomers and tau toxicity in neurodegenerative disease. Biochem Soc Trans. 2012;40(4):667-71.
Wei S, Kozono S, Kats L, et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med. 2015;21(5):457-66.
Wischik CM, Crowther RA, Stewart M, Roth M. Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol. 1985;100(6):1905-12.
Xia CF Arteaga J, Chen G, et al. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Alzheimers Dement. 2013;9(6):666-76.
Yanamandra K, Jiang H, Mahan TE, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015;2(3):278-88.
Zempel H, Luedtke J, Kumar Y, et al. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013;32(22):2920-37.
Zhang W, Arteaga J, Cashion DK, et al. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis. 2012;31(3):601-12.
Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35.
Book
National Institute on Aging, National Institutes of Health. Alzheimer's Disease: Unraveling the Mystery. Online Publication; 2011.
Organizers
Robert Martone
St. Jude Children's Research Hospital
publications
Robert Martone conducts biomarker research and development with a focus on neuro-oncology in the Department of Pathology at St. Jude Children's Research Hospital. He was previously the neuroscience therapeutic area lead for the Covance Biomarker Center of Excellence. He has expertise in both small-molecule and protein therapeutics and extensive experience in the pharmaceutical industry, leading neuroscience drug discovery and technology teams from target identification through clinical trials. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies and CNS tumor biomarker development.
Sonya Dougal, PhD
The New York Academy of Sciences
Sonya Dougal is the director of Life Sciences Discussion Groups at the New York Academy of Sciences. She develops an annual portfolio of scientific symposia on life sciences and biomedical research. Dougal has over 14 years of experience in scientific research and program management in academia, industry, and nonprofits. She holds a PhD in cognitive psychology from the University of Pittsburgh. She was the recipient of a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health for her postdoctoral training as a cognitive neuroscientist in the laboratory of Elizabeth Phelps at New York University.
Speakers
George S. Bloom, PhD
University of Virginia
website | publications
Peter Davies, PhD
Feinstein Institute for Medical Research
website | publications
Marc I. Diamond, MD
University of Texas Southwestern Medical Center
website | publications
Michael Hutton, PhD
Eli Lilly and Company
publications
Khalid Iqbal, PhD
New York State Institute for Basic Research in Developmental Disabilities
website | publications
Hartmuth C. Kolb, PhD
Johnson & Johnson, Janssen R&D
publications
Nicole Leclerc, PhD
Université de Montréal, Canada
website | publications
Kun Ping Lu, MD, PhD
Harvard Medical School
website | publications
Richard M. Ransohoff, MD
Biogen
website | publications
Short Talk Presenters
Magdalena J. Kiprowska, MS
Hunter College and Graduate Center, CUNY
publications
Natura Myeku, PhD
Taub Institute for Alzheimer's Disease Research, Columbia University
publications
Caitlin McOmish, PhD
Caitlin McOmish is a program manager at the New York Academy of Sciences.
