Neurofibrillary tangles are one of the primary hallmarks of Alzheimer disease, and closely correlate with clinical severity. They consist of hyperphosphorylated tau that aggregates in the neuronal cell body. Cross sectional histological studies suggest that tangles kill neurons. Tau disaggregation is thus a major target of the pharmaceutical industry, with at least one drug already in human clinical trials. However, recent data suggest that tangles may not be toxic. We propose to test an alternative hypothesis, in which soluble tau induced toxicity leads to activation of apoptosis related cascades, followed by tangle formation. In order to test this model, we have developed in vivo multiphoton based longitudinal imaging techniques for tangles, caspase activation, and propidium iodide (a marker of loss of membrane integrity).
Aim 1 applies this approach to Tg4510 P301L tau mice that develop NFT and neuronal loss. Surprisingly, we see caspase activation that appears to precede and predict tangle formation. We will also use array tomography, an advanced microscopic method using ultrathin sections of tissue, to determine the characteristics of the caspase positive, tangle negative cells to test the hypothesis that kinase activation leads to phosphorylation of tau, and that caspase activation leads to the truncation of tau -the combination of which causes tau aggregation into a tangle. We will use gene transfer and pharmacological studies to further dissect this pathway, to ask whether caspase activation, and caspase truncation of tau, are necessary or sufficient to cause tangle formation, neuronal distress or death.
Aim 2 asks if NFT remain in viable cells and are long lived, or if they are toxic to the neurons in which they are found either in terms of structure or function. These experiments take advantage of the power of longitudinal in vivo multiphoton imaging to follow the fate of individual tangle bearing neurons for weeks to months. We will also test the hypothesis that tangle bearing neurons are excluded from participation in normal neural system activation from physiological stimuli by exposing animals to an enriched environment, then examining individual neurons in hippocampal subfields for immediate early gene (Arc) expression and the presence or absence of tangles.
Aim 3 will rigorously test the hypothesis that wild type, nonmutant tau, undergoes similar phenomenon and that the toxic effects of tau over expression are due, in large part, to soluble tau. We take advantage of 3 models: examination of an alternative transgenic model, the hTau mice which express a minigene of wild type human tau (on a tau null background), introduction of wild type tau (or truncated forms of tau) into wild type mice using gene transfer approaches with AAV2 gene vectors, and the Tg4510 mice, which harbor a tet-response element driving the tau gene. These models allow comparison of wild type and mutant tau, and will also allow us to distinguish te effects of soluble tau from those of misfolded or aggregated tau. Taken together, our proposed studies will test the hypotheses that a non-tangle related mechanism of tau toxicity initiates apoptotic cascades, and that tangles may be a relatively nontoxic, long lived species. The results will have direct impact on design of therapeutic agents destined for clinical trials.

Public Health Relevance

Neurofibrillary tangles are widely believed to be the cause of neuronal death in Alzheimer disease, and so the cause of the dementia symptoms that mark this common and devastating disease. The current application will examine the molecular and temporal relationships between neurofibrillary tangles, neuronal death and neuronal dysfunction using advanced microscopy methods and model systems. Based on these results, therapies aimed at reducing the damage done by neurofibrillary tangles will be explored, in an attempt to better understand what causes the damage and how to prevent it.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026249-08
Application #
8313980
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Marilyn
Project Start
2004-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$436,700
Indirect Cost
$146,513
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Spires-Jones, Tara L; Friedman, Taylor; Pitstick, Rose et al. (2014) Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett 562:63-8
Kuchibhotla, Kishore V; Wegmann, Susanne; Kopeikina, Katherine J et al. (2014) Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci U S A 111:510-4
Rudinskiy, Nikita; Hawkes, Jonathan M; Wegmann, Susanne et al. (2014) Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses. Acta Neuropathol Commun 2:63
Polydoro, Manuela; Dzhala, Volodymyr I; Pooler, Amy M et al. (2014) Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model. Acta Neuropathol 127:257-70
Kopeikina, Katherine J; Polydoro, Manuela; Tai, Hwan-Ching et al. (2013) Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521:1334-53
Polydoro, Manuela; de Calignon, Alix; Suarez-Calvet, Marc et al. (2013) Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease. J Neurosci 33:13300-11
Pooler, Amy M; Polydoro, Manuela; Wegmann, Susanne K et al. (2013) Tau-amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid-induced disruption of axonal projections and exacerbated axonal pathology. J Comp Neurol 521:4236-48
de Calignon, Alix; Polydoro, Manuela; Suarez-Calvet, Marc et al. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685-97
Spires-Jones, Tara L; de Calignon, Alix; Meyer-Luehmann, Melanie et al. (2011) Monitoring protein aggregation and toxicity in Alzheimer's disease mouse models using in vivo imaging. Methods 53:201-7
Fox, Leora M; William, Christopher M; Adamowicz, David H et al. (2011) Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model. J Neuropathol Exp Neurol 70:588-95

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