Presentation Abstract

Program#/Poster#: 351.23/U2
Presentation Title: Propagation of tau pathology in a model of early Alzheimer's disease
Location: Hall A-C
Presentation time: Monday, Nov 14, 2011, 10:00 AM -11:00 AM
Authors: *M. POLYDORO1, A. DE CALIGNON1, M. SUÁREZ-CALVET2, C. WILLIAM1, D. H. ADAMOWICZ1, K. J. KOPEIKINA1,3, R. PITSTICK4, K. H. ASHE5, G. A. CARLSON4, T. L. SPIRES-JONES1, B. T. HYMAN1;
1MassGeneral Inst. for Neurodegenerative Dis. (MIND), MGH/Harvard Med. Sch., Charlestown, MA; 2Dept. of Neurology, Hosp. de la Santa Creu i Sant Pau, Univ. Autònoma de Barcelona., Barcelona, Spain; 3Dept. of Anat. and Neurobio., Boston Univ. Sch. of Med., Boston, MA; 4McLaughlin Res. Inst., Great Falls, MT; 5Dept. of Neurol., Univ. of Minnesota Med. Sch., Minneapolis, MN
Abstract: The tauopathies, which include Alzheimer’s disease and numerous degenerative disorders, are characterized by deposits of abnormally phosphorylated and misfolded protein tau called neurofibrillary tangles (NFT). In Alzheimer’s disease patients, tau pathology appears first in layer II of the entorhinal cortex (EC) and then spreads to the hippocampus and specific cortical areas. The basis of this pattern of stepwise hierarchical vulnerability is unknown. Three possibilities have been suggested: (1) there could be intrinsic differences in regional vulnerability to pathology; (2) pathological changes could potentially spread via trans-synaptic propagation of misfolded proteins or (3) deafferentation or disruption of neural system function could lead to progressive degeneration. We describe a transgenic mouse model in which expression of human tau P301L is restricted to only a subset of the stellate neurons in layer II of entorhinal cortex (EC-II). Human tau proteins were transported to the axon terminals, in the projection zone, where they accumulate from a very early age. Tau pathology slowly progressed, could be visualized by later stage epitopes, and accumulated in the neuronal cell bodies. Over the next 2 years, tangles appeared in areas that receive direct synaptic input from the EC-II such as granule cells of dentate gyrus, CA fields of the hippocampus, and cingulate gyrus, even though no transgene expression could be detected. Spread of tau pathological proteins locally, into neurons within entorhinal cortex that did not express the transgene also was observed. With age, signs of degeneration appeared in the entorhinal target zone in the molecular layer of the dentate gyrus. These data suggest that tau pathological changes progress both via local and anterograde anatomical pathways, and by causing upstream plasticity induced changes, indicative of neural system failure.
Disclosures:  M. Polydoro: None. A. de Calignon: None. M. Suárez-Calvet: None. C. William: None. D.H. Adamowicz: None. K.J. Kopeikina: None. R. Pitstick: None. K.H. Ashe: None. G.A. Carlson: None. T.L. Spires-Jones: None. B.T. Hyman: None.
Keyword(s): TAU
ALZHEIMER'S DISEASE
TRANSGENIC MOUSE
Support: NIH Grant AG08487
NIH Grant AG026249
NIH Grant K99AG33670
NIH Grant K08NS069811
[Authors]. [Abstract Title]. Program No. XXX.XX. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.

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