Neurodegeneration Exploring Commonalities Across Diseases: Workshop Summary (2013) / Chapter Skim
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4 Transmissibility
4 Transmissibility
Pages 33-44
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The progressive accumulation of protein aggregates is the pathological hallmark of many neurodegenerative diseases (see Table 2-1 and Chapter 3)
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The model is borrowed from what is known about the formation of misfolded amyloid proteins known as "prions" that are responsible for aggregating and spreading transmissible spongiform encephalopathies. The amyloid aggregates in transmissible FIGURE 4-1 a-Synuclein mediated neurodegeneration.
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It then discusses the transmissibility of specific aggregated proteins in relation to certain neurodegenerative diseases, before examining the potential success of passive immunization to counter transmission within the brain. Prion Diseases and Their Transmission Both transmissible spongiform encephalopathies and neurodegenerative diseases are marked by insoluble protein aggregates made up of misfolded protein.
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The process is accelerated by the addition of exogenous seeds. Misfolded prion proteins, oligomers, and aggregates are, in his view, "seeding competent," but the fine details of the seeding and transmission process are still elusive.
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Transmissibility of Specific Aggregated Proteins in Select Neurodegenerative Diseases This particular portion of the workshop focused on Aβ amyloid and tau transmission in Alzheimer's disease, and α-Synuclein transmission in Parkinson's disease. In describing the choice to focus on these specific topics, Trojanowski, chair of this session, noted, "We could have done more, but we as a group thought it was helpful to focus on areas that had made the most progress in cells and animal models." Aβ Amyloid Transmission in Alzheimer's Disease Lary Walker of Emory University described his research on the seeding process and the transmission of Aβ amyloid within the brain of Alzheimer's animal models.
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Tau Transmission in Alzheimer's Disease Tau is a microtubule-associated protein that aggregates in its hyperphosphorylated form into neurofibrillary tangles that are a pathological signature of Alzheimer's disease. In this disease there is a characteristic progression of neurofibrillary tangles, starting in the entorhinal cortex in prodromal stages, proceeding to the limbic areas in early to moderate stages, and finally converging on the neocortex in late stages (see Figure 4-2)
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In the future, she would like to employ her transgenic mouse model to study interactions between Aβ amyloid and tau in the entorhinal cortex and she would like to understand the mechanisms of cell-to-cell spread as well as the functional impact of tau pathology. α-Synuclein Transmission in Parkinson's and Other Neurodegenerative Diseases α-Synuclein is a cytosolic protein thought to participate in the regulation of synaptic transmission and synaptic plasticity (Murphy et al., 2000)
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Her team injected preformed fibrils and lysate from symptomatic animals into the stratum and/or cortex of asymptomatic transgenic mice. The recipient mice, which normally become symptomatic with Parkinson's-like motor impairment at 12 months of age, displayed motor impairment earlier.
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. For the study of the efficacy of immunization, Games and her colleagues selected a transgenic mouse model expressing α-Synuclein because mice develop behavioral deficits and α-Synuclein aggregates throughout the temporal cortex and hippocampus similar to what has been described in Lewy body disease.
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These mice are commonly used, said Davies, because they show many of the features of frontotemporal dementia and their tau pathology appears early. Using this mouse model, Davies and his colleagues revealed that antibodies directed at tau reduce pathology in the hippocampus and delay progression of disease (Chai et al., 2011)
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• For trials using anti-tau antibodies, test therapies in patients with pure tauopathy, such as frontotemporal dementia or progressive supranuclear palsy. (Davies)
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