P3‐226: Elimination of APP caspase cleavage site D664 attenuates Aβ‐mediated synaptic depression

accumulating as intraand extracellular oligomers and deposits; (ii) fibrillar aggregates of hyper-phosphorylated protein tau in neuropil threads and tangles. It is generally accepted that AD-pathology and defects originate in the entorhinal cortex (ERC), spreading towards the hippocampus in later stages. It is surmised that amyloid and/or tau pathology can make use of the perforant pathway (PP) and the temporo-ammonic (TA) pathway. TA projects central to the CA1 of the hippocampus by axons originating in ERC layer III that end in the synapses of the stratum lacunosum moleculare (SLM). The SLM is thus considered as a region of major interest in AD. We observed that Nectin-3, a major cell-adhesionmolecule (CAM) for glutamatergic synapses in the hippocampus, is lacking in the SLM of tau.P301L transgenic mice. Methods: We analyzed the defect in Nectin-3 in SLM by a multi-disciplinary approach, including functional, structural and biochemical methods. We analyzed levels of tau expression and phosphorylation in transgenic tau.P301L mice, and in the bigenic combination with GSK3s[S9A] (biGT mice)(Spittaels et al, 2000; Terwel et al, 2005, 2008). Results: Levels of CAM Nectin-3 are strongly decreased in CA1 SLM, assessed by immunohistochemistry in tau.P301L mice. Moreover, a similar selective decrease in Nectin-3 levels in SLMwas observed in the more acute viral AAV-model (Jaworski et al, 2009): already 10 days after intra-hippocampal injection of AAV-Tau. In-situ hybridization revealed that Nectin-3 mRNA levels were significantly decreased in the lateral ERC layers II to V, in Tau.P301L mice, and in the hippocampus. Therefore it appears that Nectin-3 is present in both preand post-synaptic compartments, originating respectively in CA1 and ERC neurons. Further evidence stems from morphological changes in spines at light and ultra structural levels, in this central region of the hippocampus, that become evident prior to the occurrence of the fibrillar tauopathy. The spine maturation index in SLM is decreased in tau.P301L mice relative to wild-type mice and on par with that in CA1 stratum radiatum. Finally, myelinated axons in the SLM show extended disruption of their myelin sheets in tau.P301L mice, progressing with age, which appears linked to increased inflammation. Remarkably, this aspect is aggravated in the biGT mice, which suffer not only more intense SLM myelinization defects but also markedly earlier and more intense inflammation in the hippocampus and SLM. Conclusions:We observed that axons and synapses in the SLM, the major input region of the entorhinal cortex to the hippocampus, is affected by expression of the protein tau in transgenic and in AAV-tau mouse models. The loss of synaptic Nectin-3 specifically marks the SLM, and could help explain why early functional memory defects are observed before the onset of the fibrillar tau-pathology in tau.P301L mice, in GSK3xtau.P301L mice and in AAV-tau injected mice.