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Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

After more than a year of unrest, a small effusive eruption commenced in Fagradalsfjall, Iceland, on 19 March 2021. The eruption lasted six months. The first six weeks were characterized by multiple fissure openings, and the remainder was dominated by effusive activity from a single crater. During the eruption, lava and low-level gases propagated over the complex terrain: a hyaloclastite massif with mountain peaks up to about 350 m asl with valleys in between. The area is uninhabited, but easily accessible at about 30 km distance from Reykjavík. While the eruption was ongoing, more than 356,000 tourists visited the eruptive site. To maintain low risk access to the area, it was critical to monitor the eruption (including opening of new fissures) in real-time, forecast the transport of gas and lava flow emplacement, and assess the evolving hazards. In addition to data accessibility and interpretation, managing this volcanic crisis was possible thanks to strong collaboration between the scientific institutions and civil protection agencies. The eruption presented an opportunity to tune, test and validate a variety of numerical models for hazard assessment as well as to refine and improve the delivery of information to the general public, communities living near the eruption site and decision makers. The monitoring team worked long hours during both the pre- and syn-eruptive phases for identifying low risk access areas to the eruption site and to provide a regular flow of information. This paper reviews the eruption and its associated hazards. It also provides an overview of the monitoring setup, the adopted numerical tools and communication materials disseminated to the general public regarding current exclusion zones, hazards and possible future eruptive scenarios.

Cerebral amyloid-β (Aβ) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Aβ related toxicity being linked to its β-sheet conformation and/or aggregation. We show that a β-sheet breaker peptide (iAβ5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAβ5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Aβ and reduced the extent of interleukin-1β positive microglia-like cells that surround the Aβ deposits. These findings suggest that β-sheet breakers, such as iAβ5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Aβ-related histopathology.

Transgenic mice with brain amyloid-β (Aβ) plaques immunized with aggregated Aβ1-42 have reduced cerebral amyloid burden. However, the use of Aβ1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Aβ homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% ( P = 0.0002) and 81% ( P = 0.0001), respectively. Concurrently, brain levels of soluble Aβ1-42 were reduced by 57% ( P = 0.0019). Ramified microglia expressing interleukin-1β associated with the Aβ plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Aβ derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Aβ fibrils.

Inhibition of cerebral amyloid β-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as β-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid βprotein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the β-sheet breaker peptide significantly reduces amyloid βprotein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease.

We have observed that single amyloid-β 25-35 (Aβ) injections (5.0 nmol) into the right amygdala of rats produce progressive cytoskeletal and astrogliotic reactions not only within the amygdala, but also in distal brain regions that project to the amygdala. To determine if these effects are potentiated by bilateral injections, we injected Aβ (5.0 nmol) into the left and right amygdala of young male Fischer rats. Animals were sacrificed 32 days postoperatively. Bilateral infusions of Aβ induced significant neuronal shrinkage, tau-2 neuronal staining, and reactive astrocytosis within the right amygdala and/or hippocampus, compared with vehicle-treated rats. Surprisingly, the same brain regions within the left hemisphere were significantly less affected even though no differences were observed between the left and right amygdala in the size of Congored-positive Aβ deposits. Unilateral injections of Aβ into the left amygdala led to significant histological changes in the right amygdala and hippocampus, but not in the same brain regions within the left hemisphere. These results suggest a laterality in the histopathological effects of Aβ in male Fischer rats. Identification of the cause for the lateralized effect of Aβ may prove valuable for understanding the etiology of Alzheimer disease and provide possible therapeutic strategies designed to slow the progression of the disease.

It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid β (Aβ) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Aβ precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Aβ and massive Aβ deposition into plaques. At this stage, IDE appeared surrounding Aβ fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Aβ-mediated inflammation process. When primary astrocytes were exposed to fibrillar Aβ in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Aβ-triggered inflammation.

The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease.

We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.

Cerebral amyloid-[beta] (A[beta]) deposition is central to the neuropathological definition of Alzheimer disease (AD) with A[beta] related toxicity being linked to its [beta]-sheet conformation and/or aggregation. We show that a [beta]-sheet breaker peptide (iA[beta]5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iA[beta]5-induced disassembly prevented and/or reversed neuronal shrinkage caused by A [beta] and reduced the extent of interleukin-1[beta] positive microglia-like cells that surround the A [beta] deposits. These findings suggest that [beta]-sheet breakers, such as iA[beta]5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing A[beta]-related histopathology.