Tau-mediated synaptic dysfunction is likely

to be a key step in the transition from the asymptomatic to symptomatic phase of tauopathies, the former phase characterized by changes in functional and molecular biomarkers, the latter phase characterized by neuronal death and cognitive deficits. Our electrophysiological and immunocytochemical experiments revealed that tau mutation or hyperphosphorylation leads to impaired trafficking or anchoring of AMPARs and NMDARs that precedes spine loss. Understanding the early pathological FG-4592 nmr events preceding synapse loss in neurodegenerative diseases is of critical relevance since synaptic loss correlates more robustly with cognitive deficits in AD than plaque or tangle load (Davies et al., 1987, Terry et al., 1991, Masliah et al., 2001 and Selkoe, 2002). Most excitatory synaptic transmission is mediated through dendritic spines which are principal loci of synaptic plasticity (Hering and Sheng, 2001). Glutamatergic receptors govern the morphological plasticity of spines with NMDARs regulating the formation of new spines and AMPARs stabilizing established spines (Fischer et al., 2000). Interestingly, a recent study demonstrated that tau decreased NMDAR expression in the PSD complex,

though no alterations in NMDAR-mediated currents were detected (Ittner et al., 2010). Our study complements and extends these findings to include tau-induced impairments in synaptic targeting or anchoring of AMPARs and AMPAR-mediated synaptic currents.

check details Dendritic spine stability is compromised by loss of synaptic AMPARs, leading to spine loss (McKinney et al., 1999 and Richards et al., 2005; for review, see McKinney, 2010). Despite the strong correlation between loss of spines and Mannose-binding protein-associated serine protease synaptic AMPARs, the temporal relationship between these two physiological events is not well-defined. It has also been reported that these two cellular processes can be dissociated (Sdrulla and Linden, 2007 and Wang et al., 2007). Although other studies (Shahani et al., 2006 and Tackenberg and Brandt, 2009) have also failed to observe tau-mediated spine loss, the state of synaptic AMPARs was not reported in these papers. Thus, we hypothesize that the absence of spine loss, despite decreased synaptic AMPARs, is due to the very early nature of the tau-induced synaptic impairments. A similar theory was proposed in a study using the APPswe/PS1 dE9 transgenic mouse model of AD (Shemer et al., 2006). The relationship between Aβ-induced early synaptic dysfunction and tau-mediated global disruption of glutamate receptors remains to be determined. A recent report (Zempel et al., 2010) suggests that spines might serve as a site of convergence for amyloid beta and tau.