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.
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