While Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are distinct diseases;we suspect that they share certain pathogenic mechanisms, particularly abnormalities in the intracellular distribution of cargoes that regulate synaptic activity. In some forms of FTLD, these abnormalities may result from specific mutations in the microtubule-associated protein tau that imparts gains of adverse function. In AD, they may result from indirect pathogenic interactions between wildtype tau and amyloid-? (A?) peptides, which are widely thought to cause AD. This etiologic difference may account, at least in part, for the fact that these conditions affect different neuronal populations. Identifying common molecular mechanisms in AD and FTLD might help preserve both of these neuronal populations. We hypothesize that impairments of axonal transport by A? and wildtype tau in AD and by mutant tau in FTLD require interactions of tau with the tyrosine kinase Fyn. We further hypothesize that A? and tau cause abnormal distribution of NMDA receptors (NMDARs) in dendritic spines, at least in part, by increasing the Fyn/ephB2 tyrosine kinase ratio in the postsynaptic density. These pre- and postsynaptic mechanisms are not mutually exclusive. They might result from Fyn-mediated effects on tau, tau-mediated effects on Fyn, or both, and could contribute to A?- and tau-dependent neurological deficits in dementing disorders. To assess these possibilities, we propose to Aim 1. determine whether interactions between tau and Fyn are required for A? and tau to impair synaptic and behavioral functions;
Aim 2. determine whether interactions between tau and Fyn are required for A? and tau to impair axonal transport and to reduce the ratio of intrasynaptic to extrasynaptic NMDARs;
and Aim 3. determine whether ephB2 protects against A?-induced neuronal dysfunction by increasing the ratio of intrasynaptic to extrasynaptic NMDARs and whether ephB2's protective capacity depends on kinase activity. We hypothesize that human A? oligomers and FTLD-mutant tau will no longer impair synaptic and behavioral functions when interactions (binding or phosphorylation) between Fyn and tau are blocked (Aim 1). We further hypothesize that this protective effect involves at least two mechanisms: improvements in the axonal transport of synaptic activity-related proteins (Aim 2a) and increases in the ratio of intrasynaptic to extrasynaptic NMDARs (Aim 2b). We suspect that the latter mechanism also accounts for the ability of ephB2 to protect against A?-induced neuronal dysfunction (Aim 3). The proposed experiments will test a number of mechanistic hypotheses that have not yet been tested conclusively and address questions to which there currently are no firm answers. The answers we expect to obtain will shed light on the mechanisms that cause neurological decline in AD and FTLD and could help identify novel strategies to prevent and reverse these devastating diseases.
The protein tau has been implicated in the etiology of Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and a variety of other neurodegenerative conditions referred to as "tauopathies." Preliminary data obtained during the preceding funding period suggest that neuronal and behavioral impairments in AD and FTLD may result from overlapping mechanisms affecting the intracellular distribution of proteins that regulate synaptic activity. The proposed experiments aim to unravel these mechanisms and could help identify novel strategies to prevent and reverse these devastating conditions.
|Miyamoto, Takashi; Kim, Daniel; Knox, Joseph A et al. (2016) Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-Î²-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity. J Biol Chem 291:1719-34|
|Maeda, Sumihiro; Djukic, Biljana; Taneja, Praveen et al. (2016) Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Rep 17:530-51|
|Morris, Meaghan; Knudsen, Giselle M; Maeda, Sumihiro et al. (2015) Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci 18:1183-9|
|Dubal, Dena B; Zhu, Lei; Sanchez, Pascal E et al. (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci 35:2358-71|
|Vossel, Keith A; Xu, Jordan C; Fomenko, Vira et al. (2015) Tau reduction prevents AÎ²-induced axonal transport deficits by blocking activation of GSK3Î². J Cell Biol 209:419-33|
|Gheyara, Ania L; Ponnusamy, Ravikumar; Djukic, Biljana et al. (2014) Tau reduction prevents disease in a mouse model of Dravet syndrome. Ann Neurol 76:443-56|
|Cheng, Jason S; Craft, Ryan; Yu, Gui-Qiu et al. (2014) Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice. PLoS One 9:e115765|
|Roberson, Erik D; Halabisky, Brian; Yoo, Jong W et al. (2011) Amyloid-Ã½Ã½/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31:700-11|
|Morris, Meaghan; Maeda, Sumihiro; Vossel, Keith et al. (2011) The many faces of tau. Neuron 70:410-26|
|CissÃ©, Moustapha; Halabisky, Brian; Harris, Julie et al. (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469:47-52|
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