Key Points
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Amyloids can be broadly defined as insoluble protein aggregates containing a characteristic highly ordered, β-sheet-rich structural motif. The latter can be identified histologically with dyes such as Congo Red and thioflavin. Some amyloids may have an adaptive physiological function; however, most amyloids are thought to be abnormal and are associated with a range of clinical pathologies including systemic amyloidoses and some neurodegenerative disorders.
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Alzheimer's disease, the most common neurodegenerative disorder, is currently the focus of some of the most exciting and rapidly progressing research on amyloid therapeutics. Two main approaches are being pursued to deplete cerebral amyloid β (Aβ) levels, the primary component of senile plaques associated with Alzheimer's disease. The first approach involves inhibition of the secretases responsible for Aβ production. The second approach involves mobilization of the immune system to promote Aβ clearance.
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Aβ is produced from the sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretase. The development of small-molecule inhibitors for these enzymes or complexes as a therapeutic method of depleting monomeric Aβ from the brain has met with considerable success, as well as several challenges. Most notably, the secretases have other non-APP substrates (for example, γ-secretase cleavage of Notch and β-secretase cleavage of Neuregulin 1) that are important for normal physiology.
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Enhanced clearance of monomeric Aβ and Aβ aggregates by Aβ immunotherapy has been used successfully to lower cerebral Aβ levels and promote cognitive improvement in murine amyloid models. Initial attempts to actively immunize against Aβ in humans were suspended owing to the development of adverse immune responses in some patients. However, passive immunotherapeutic approaches have progressed to clinical trials, and administration of intravenous immunglobulins may also be effective for lowering Aβ levels in the brain.
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Increasing evidence implicates specific forms of Aβ (for example, soluble Aβ oligomers and intraneuronal Aβ) in Alzheimer's disease-associated neurotoxicity, raising the intriguing possibility that therapies targeted at these pools of Aβ (for example, conformation-specific antibodies) may be effective in ameliorating cognitive deficits associated with Alzheimer's disease by blocking cell death pathways rather than altering Aβ homeostasis.
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Prion diseases are the only known amyloidoses that act as genuine infectious diseases, with the possible exception of AA amyloidosis. The unusual properties of prion amyloid have presented significant challenges for therapeutics, as well as some opportunities to explore unique therapeutic modalities.
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In many cases of acquired prion disease, prions first colonize and replicate in extraneural secondary lymphoid organs before being transmitted to the central nervous system (CNS). Blockade of prion replication at these extraneural sites (for example, by inhibition of lymphotoxin β receptor (LTβR) signalling) is an effective method to prevent the spread of prions from the periphery to the CNS and may be useful for post-exposure prophylaxis against prion infections.
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Attempts to generate active immune responses against PrPSc (PrP with abnormal conformation) have had little success owing to immune tolerance of ubiquitously expressed endogenous PrPC(PrP with normal conformation). However, passive immunization with large doses of PrP antibodies isolated from Prnp−/− mice can prevent the spread of prions from the periphery to the CNS upon intraperitoneal inoculation. It has not yet been demonstrated that PrP immunotherapy is effective in slowing the rate of prion disease once it has reached the CNS. However, the development of PrP antibodies that effectively cross the blood–brain barrier may dramatically enhance the efficacy of PrP immunotherapy for the treatment of CNS prion infections.
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Numerous compounds have been investigated or are being developed for their anti-aggregation properties including various amyloid-binding dyes, anti-malarial compounds, protein X mimetics, β-sheet breakers and scyllo-inositol. These compounds are still in development for the treatment of prion diseases and other neurodegenerative disorders; however, some of these compounds are currently in clinical trials for the treatment of systemic amyloidoses.
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Several lines of evidence indicate that protein aggregates trigger specific cellular toxicity pathways in the brain, including the resistance of non-neuronal cell types and Prnp−/− neurons to PrPSc-induced toxicity. Intriguingly, PrPC was recently identified as a receptor for oligomeric Aβ, suggesting that diverse protein aggregates may activate common neurotoxicity pathways, which may have important therapeutic implications for amyloid diseases.
Abstract
A growing number of diseases seem to be associated with inappropriate deposition of protein aggregates. Some of these diseases — such as Alzheimer's disease and systemic amyloidoses — have been recognized for a long time. However, it is now clear that ordered aggregation of pathogenic proteins does not only occur in the extracellular space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also qualify as amyloidoses. The common structural and pathogenic features of these diverse protein aggregation diseases is only now being fully understood, and may provide novel opportunities for overarching therapeutic approaches such as depleting the monomeric precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking common aggregation-induced cellular toxicity pathways.
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Acknowledgements
Stained sections from human Alzheimer's diseased brains, prion-diseased brains, kidney amyloidosis, and the PrPSc histoblot were provided courtesy of J. Haybaeck, H. Fischer, V. Kana and M. Heikenwälder of the Institute for Neuropathology at the University Hospital of Zürich, Switzerland. The Aguzzi laboratory is supported by grants of the Ernst-Jung-Foundation, the Stammbach foundation, the EU (LUPAS, PRIORITY), the Swiss National Science Foundation, a Sinergia grant, and the National Competence Center on Neural Plasticity and Repair. A.A. is a recipient of an Advanced Grant of the European Research Council.
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- Blood–brain barrier
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A protective wall of capillary epithelium separating the brain parenchyma from the bloodstream that is impenetrable to most circulating substances.
- Passive transfer
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A process by which a host acquires exogenous antibodies and hence immunity to an immunogen without generating an active immune response.
- Long-term depression
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An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.
- Long-term potentiation
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A persistent increase in synaptic response following repeated stimulation of a neuron, which is thought to be associated with synaptic plasticity and the acquisition of memories.
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Aguzzi, A., O'Connor, T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov 9, 237–248 (2010). https://doi.org/10.1038/nrd3050
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DOI: https://doi.org/10.1038/nrd3050
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