Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models

Abstract

Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

“…6B and C). Similarly, ablation of the microtubule‐associated protein tau, which has been shown to reduce epileptic activity in a variety of seizure models,28, 30, 31, 32, 33, 34 tended to reduce interictal events by roughly 50% but, if anything, tended to slightly increase the left shift in spectral power in SYN mice (Fig. 6D and E).…”

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…The molecular basis for these alterations is unclear, but they are indicative of a redistribution of synaptic weights, which is consistent with the bidirectional effect of PSD size that we also observed in these neurons. In fact, Tau is present in dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014). In these structures, it has been shown that activation of NMDA glutamate receptor triggers Tau phosphorylation, thus regulating the interaction of Tau with the actin cytoskeleton, PSD95, and Fyn kinase (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014).…”

“…It plays key roles in the establishment of neuronal polarity and migration during embryonic development (Caceres & Kosik, 1990; Dawson et al , 2001; Sapir et al , 2012; Sayas et al , 2015), in axonal transport (Ballatore et al , 2007; Hernandez & Avila, 2010) and in intracellular trafficking (Hernandez & Avila, 2010). Under physiological conditions, Tau is located mainly in axonal microtubules (Hirokawa et al , 1996; Aronov et al , 2001), although increasing evidence supports its presence also in dendrites (Ittner et al , 2010) and dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Kimura et al , 2014). The affinity of Tau to bind microtubules is finely regulated, depending mainly on the selective expression of various isoforms and post‐translational modifications.…”

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…Indeed, we observed hTau‐A152T‐dependent neuronal loss in the hippocampus, consistent with findings obtained by Decker and colleagues 74. Mechanisms to explore in future studies include potential effects of the A152T substitution on (1) hTau/Fyn interactions 75, which could contribute to NMDA receptor‐mediated neurotoxicity 74, (2) network hyperexcitability 50, 76, and (3) tau's Gly 155 –Gln 244 region, which is exposed on the surface of tau oligomers 77 and might mediate interactions between these assemblies and cellular targets.…”