Estrogens have been described to induce synaptogenesis in principal neurons of the hippocampus and have been shown to be synthesized and released by exactly these neurons. Here, we have focused on the significance of local estrogen synthesis on spine synapse formation and the synthesis of synaptic proteins. To this end, we reduced hippocampal estrogen synthesis in vitro with letrozole, a reversible nonsteroidal aromatase inhibitor. In hippocampal slice cultures, letrozole treatment resulted in a dose-dependent decrease of 17␤-estradiol as quantified by RIA. This was accompanied by a significant decrease in the density of spine synapses and in the number of presynaptic boutons. Quantitative immunohistochemistry revealed a downregulation of spinophilin, a marker of dendritic spines, and synaptophysin, a protein of presynaptic vesicles, in response to letrozole. Surprisingly, no increase in the density of spines, boutons, and synapses and in spinophilin expression was seen after application of estradiol to the medium of cultures that had not been treated with letrozole. However, synaptophysin expression was upregulated under these conditions. Our results point to an essential role of endogenous hippocampal estrogen synthesis in the maintenance of hippocampal spine synapses.

The miniaturization of magnetic devices toward the limit of single atoms calls for appropriate tools to study their magnetic properties. We demonstrate the ability to measure magnetization curves of individual magnetic atoms adsorbed on a nonmagnetic metallic substrate with use of a scanning tunneling microscope with a spin-polarized tip. We can map out low-energy magnetic interactions on the atomic scale as evidenced by the oscillating indirect exchange between a Co adatom and a nanowire on Pt(111). These results are important for the understanding of variations that are found in the magnetic properties of apparently identical adatoms because of different local environments.

Ruderman-Kittel-Kasuya-Yosida interaction [1][2][3] is an indirect magnetic coupling between localized spins in a non-magnetic host mediated by conduction electrons. In diluted systems it is often the dominating magnetic interaction and has played a key part in the development of giant magnetoresistance devices 4,5 , drives ferromagnetism in heavy rare-earth elements 6 as well as in diluted magnetic semiconductors 7 and gives rise to complex magnetic phases such as spin glasses 8 . For bulk systems, an isotropic and continuous model of Ruderman-Kittel-KasuyaYosida interaction is often sufficient. However, it can be misleading in magnetic nanostructures consisting of separate magnetic atoms adsorbed on the surface of a non-magnetic material. Here, an atomically precise map of the magnetic coupling between individual adatoms in pairs is measured and directly compared with first-principles calculations, proving that Ruderman-Kittel-Kasuya-Yosida interaction is strongly directional. By investigating adatom triplets of different shapes we demonstrate that the map can serve to tailor the magnetism of larger nanostructures.Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction is ubiquitous in solid-state systems containing diluted magnetic moments in a conducting non-magnetic host. It becomes dominant whenever there is a sufficiently strong exchange coupling between the localized moments and the conduction electrons. Then, the spins of the conduction electrons, which are on average unpolarized, are forced into a preferred direction in the vicinity of each moment. This preferential direction oscillates with increasing distance from the moment. A second localized moment will interact with this spin-density oscillation and perceive either a ferromagnetic or an antiferromagnetic coupling to the first, depending on their distance. Therefore, RKKY interaction is also called indirect magnetic exchange. The first indications of indirect magnetic exchange through conduction electrons came with the research on diluted bulk alloys, where a dependence of the interaction strength on the distance between the moments with an oscillation period of half the Fermi wavelength was proposed in an isotropic and continuous model [1][2][3] . Direct experimental evidence for RKKY-like coupling of magnetic layers through transition-metal layers was obtained by spatial-averaging techniques [9][10][11][12] . There have been theoretical [13][14][15] and experimental 16 hints that accurate RKKY models have to take into account the topology of the Fermi surface and the discrete distribution of magnetic moments on the atomic lattice, but a direct experimental proof was hampered by the spatial averaging, which provides only fragmentary information on the distribution. However, as magnetic devices are becoming smaller and approaching the limit of nanostructures built by separate atoms, knowledge of the RKKY interaction on the atomic scale is essential.By using scanning tunnelling spectroscopy, it became possible to investigate magnetic interactions in atom ...

This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau RD ). Mice were generated to express Tau RD in two forms, differing in their propensity for ␤-structure and thus in their tendency for aggregation ("pro-aggregant" or "anti-aggregant") (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the ␤-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching Tau RD on or off. The mice are normal in neuromotor tests. However, pro-aggregant Tau RD mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specificallyperturbsthesebrainfunctions.Remarkably,whentheexpressionofhumanpro-aggregantTau RD isswitchedonforϳ10monthsand off for ϳ4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau RD constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.

We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation ⌬K280 (Tau RD /⌬K280), or the ⌬K280 plus two proline mutations in the hexapeptide motifs (Tau RD /⌬K280/I277P/I308P). The ⌬K280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKII␣ (calcium/calmodulin-dependent protein kinase II␣) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2-3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau RD coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation Tau RD is switched off, soluble and aggregated exogenous Tau RD disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.