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  • The specific mechanism and neurotoxic A species

    2023-09-16

    The specific mechanism and neurotoxic Aβ Caspase-4 Colorimetric Assay Kit are yet to be elucidated, however recent studies have provided significant evidence for the amyloid channel hypothesis. These reports have established that relatively small oligomers (<10 Aβ molecules) composed of an antiparallel β-strand-β-turn-β-strand conformation exhibit elevated affinity for membranes. These intermediate states can subsequently incorporate in the membrane and assemble into a pore or channel. Interestingly, only Aβ1-42 showed the capacity to form pores in vitro, thus providing an explanation for the observed differences in neurotoxicity between both alloforms. However, this is clearly not the only mechanism of neurotoxicity, since pathogenic oligomers with parallel β-sheets have been derived from patient brains.
    Conflict of interest
    Acknowledgements This work was financed by the following collaborative grants to J.P and H.B.: PROP-AD and SequenceAD. SequenceAD is a project funded by the EEA grants Norway/Latvia through VIAA/Latvia (NFI/R/2014/023). PROP-AD is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project that is supported through the following local funding organizations under the aegis of JPND - www.jpnd.eu (AKA#301228 – Finland, BMBF#01ED1605 - Germany, CSO-MOH#30000-12631 - Israel, NFR#260786 - Norway, SRC#2015-06795 - Sweden). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND). The work of J.P is also funded by Deutsche Forschungsgemeinschaft/Germany (DFG PA930/9, DFG PA930/12); Leibniz Society/Germany (SAW-2015-IPB-2); HelseSØ/Norway (2016062); Norsk forskningsrådet/Norway (246392, 247179 (NeuroGeM), 248772, 251290); Horizon 2020/European Union (609020 (Scientia Fellows), 643417 (PROP-AD)). NeuroGeM is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND - www.jpnd.eu (CIHR – Canada, BMBF – Germany, NRF#247179 – Norway, ZonMW – The Netherlands). Scientia Fellows: The research has also received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement No 609020.
    The pathological hallmarks of Alzheimer’s disease (AD) are extracellular deposition of cerebral amyloid, predominantly composed of amyloid-β (Aβ) protein forming plaques and vascular deposits, and intracellular neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. Aβ plaques were initially suspected to be directly toxic to neurons, although closer inspection revealed that levels of plaque deposits did not necessarily correlate with the severity of disease . For this reason, attention has turned to soluble oligomeric forms of Aβ that appear to be more neurotoxic and correlate better with disease in patients with AD . The soluble Aβ forms range from monomers to high-molecular-weight aggregates with different properties and toxic effects (). It is possible that distinct conformations or classes of assemblies may also possess different seeding activity , . Similarities between AD and prion disease have been noted for decades, and the recent major growth of interest in the role of so-called prion-like mechanisms in other neurodegenerative diseases has led to an explosion in publications linking these diseases , which is beyond the scope of this review. It remains to be seen if knowledge of the misfolding and seeded aggregation processes will result in new therapeutics for sporadic forms of these diseases. However, a wider understanding of prion pathogenesis and the decades of experience accumulated in the prion field could facilitate AD research and the development of novel therapies . AD itself incorporates a melee of genetic and apparently sporadic conditions that can coexist with an ever greater number of comorbid pathologies as age at onset increases . The complexities of Aβ oligomer research have been discussed in detail elsewhere . Some arguments will be emphasized here, but all are relevant to this area of AD research. Poor reproducibility among laboratories is often blamed on poorly defined synthetic preparations loosely based on standard recipes rather than full characterization of the content of each batch produced. This common assumption can be tested only if all preparations are fully characterized when published , . A recent trend toward defining toxic Aβ assemblies by structural fingerprints, rather than the conditions in which they were produced, may help address this problem , . As AD patient samples are both precious, and inherently complex and heterogeneous, it seems pragmatic to continue to test a hypothesis with synthetic or recombinant Aβ that does not contain alternative amyloid precursor protein (APP) metabolites before confirming the relevance with human samples . Indeed, Aβ samples from AD brains will always vary in composition, concentration, and purity. Native isolation of different Aβ assemblies present in AD brain samples is complex, as purification methods can disrupt and change the conformation of aggregates . Identification of toxic receptors for such a heterologous disease will be challenging.