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P1‐355: Mechanistic studies of antibody mediated clearance of tau aggregates using an ex vivo brain slice model
Author(s) -
Krishnamurthy Pavan K.,
Deng Yan,
Mathews Paul M.,
Sigurdsson Einar M.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.909
Subject(s) - epitope , tauopathy , antibody , chemistry , microbiology and biotechnology , colocalization , tau protein , immunolabeling , linear epitope , immunohistochemistry , biology , pathology , immunology , neurodegeneration , alzheimer's disease , medicine , disease
neurodegeneration. This is an important area of investigation, which may lead to more timely and effective interventions. Methods: We investigated synaptic plasticity and the dendritic localization of human tau (htau) in the rTg4510 mouse model of tauopathy at an age (4.5M) when the mice are cognitively impaired but exhibit no overt synapse or neuron loss. Subsequently, we examined the dendritic localization of htau and synaptic function in transfected, dissociated rat hippocampal neurons. Finally, we studied surface AMPA receptors in neurons cultured from mice expressing htau. Results: We found higher concentrations of htau in the postsynaptic densities of impaired rTg4510 mice expressing htauP301L than intact rTg21221 mice expressing wild-type htauWT. This mislocalization of tau to dendritic spines also occurs to a greater extent in rat hippocampal neurons transfected with htauP301L than htauWT. Inhibiting proline-directed phosphorylation by substituting alanine at 14 serine and threonine residues blocked the mislocalization of htauP301L to dendritic spines. Conversely, pseudo-hyperphosphorylation of these 14 residues by substituting glutamate mimics htauP301L mislocalization. Spines containing htau showed decreased frequencies and amplitudes of miniature excitatory postsynaptic currents, and reduced levels of surface AMPA receptors. Conclusions: The earliest tau-related neurological deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic dysfunction arising from the mislocalization of tau to dendritic spines, which is accompanied by a reduction in surface AMPA receptors.