Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

The mechanism of γ-Secretase dysfunction in familial Alzheimer diseaseMutations in presenilin (PSEN) and amyloid precursor protein (APP) cause dominant early-onset Alzheimer's disease (AD), but the mechanism involved is debated. Here, such mutations are shown to alter γ-secretase activity, leading to changes in Aβ peptide cleavage patterns.

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus-dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsα, but not APPsβ, indicating a crucial role for APPsα to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition.

Background:The function and physiological substrates of BACE1 remain largely unknown. Results: Novel substrates for BACE1 were identified using large scale proteome analysis; L1 and CHL1 were validated in vivo. Conclusion: L1 and CHL1 are physiological substrates for BACE1. Significance: Identification of physiological substrates of BACE1 is important to understand its function and helps to predict potential side effects of BACE1 inhibitor drugs for Alzheimer disease.

tested bexarotene as a potential b-amyloid-lowering drug for Alzheimer's disease (AD). We were not able to reproduce the described effects in several animal models. Drug formulation appears very critical. Our data call for extreme caution when considering this compound for use in AD patients.

Alzheimer’s disease and frontotemporal dementia are amongst the most common forms of dementia characterized by the formation and deposition of abnormal TAU in the brain. In order to develop a translational human TAU aggregation model suitable for screening, we transduced TAU harboring the pro-aggregating P301L mutation into control hiPSC-derived neural progenitor cells followed by differentiation into cortical neurons. TAU aggregation and phosphorylation was quantified using AlphaLISA technology. Although no spontaneous aggregation was observed upon expressing TAU-P301L in neurons, seeding with preformed aggregates consisting of the TAU-microtubule binding repeat domain triggered robust TAU aggregation and hyperphosphorylation already after 2 weeks, without affecting general cell health. To validate our model, activity of two autophagy inducers was tested. Both rapamycin and trehalose significantly reduced TAU aggregation levels suggesting that iPSC-derived neurons allow for the generation of a biologically relevant human Tauopathy model, highly suitable to screen for compounds that modulate TAU aggregation.

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

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