. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med. 2020 Feb 5;12(529) PubMed.


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  1. Genetic studies have shown that the APOE ε4 allele not only markedly increases risk for Alzheimer’s disease but also strongly associates with risk for developing Lewy body dementia (LBD). The exact role of APOE in LBD, however, is poorly understood. One school of thought is that APOE drives amyloid co-pathology in LBD; alternatively, it is also possible that APOE directly triggers α-synuclein aggregation.

    To study the effect of APOE on α-synuclein, these two groups generated transgenic synucleinopathy mouse models. In the Zhao et al. study, intracerebral injection of AAV-α-synuclein into animals with different APOE backgrounds was performed, while the Davis et al. study used A53T SNCA transgenic mice on either knockout or APOE knock-in backgrounds. Remarkably, both studies found that animals with an APOEε4 background exhibited increased α-synuclein pathology with associated reactive gliosis compared with APOEε2 mice. Additionally, APOEε4 mice exhibited behavioral deficits.

    These findings are important observations as they support the hypothesis that APOEε4 not only drives Alzheimer’s disease pathology, but it also stimulates α-synuclein aggregation. Equally notable is the finding that, contrary to APOEε4, the ε2 allele appears to impart resilience to protein aggregation. What is less clear is what the exact molecular cascades are that lead to the deposition of these different proteins. Further, we do not know whether pathological β-amyloid, tau, and α-synuclein proteins are interacting and exacerbating their respective accumulations or whether these proteins aggregate independently from each other. Advancing our understanding of the genetic factors that are driving concomitant proteinopathies is crucial for the development of disease-modifying interventions.

    View all comments by Sonja Scholz
  2. These two papers support each other, and, coming from two different teams and using different approaches, that is clearly a great strength.

    When it comes to neuropathology and genetic risk, the lines between AD, DLB, and PD (especially PDD) are becoming increasingly blurred the more that we learn about these diseases. It is truly fascinating, and these two papers add important information to this developing story. One implication of the findings is that several of these neurodegenerative disorders might share common therapeutic targets. Thus, there is hope that in the future it might be possible to develop single therapies that provide disease-modifying benefit to more than one of the disorders. The emerging pattern that inflammation is a potential driver (as opposed to just a consequence of neurodegeneration) is particularly interesting. Also, the papers also touch upon the notion that proteinopathies depend on interactions with lipid homeostasis, which is another exciting emerging theme in the research field. These two insights might say something about where future disease-modifying treatments could be developed.

    The collective data in the two papers are strong and very convincing, but, as is often the case with large studies, all the datasets are not equally conclusive. For example, the data on α-synuclein preformed fibril (PFF) injections into the striatum (Fig. 6 in the Davis et al. paper) leave several unanswered questions. The authors eloquently discuss some shortcomings, and, for example, mention that they only examined one short (three months) survival time point. In this model, it would have been desirable to follow animals for six months for α-synuclein pathology and neuronal loss to fully develop in the substantia nigra. Furthermore, it appears that nigral neurons were only counted on four sections, as opposed to unbiased stereology throughout the substantia nigra. More insight would also have been gained if the nigral neurons had been stained with an additional method beyond tyrosine hydroxylase immunohistochemistry. This would clarify if cells were dying, or just displaying reduced levels of tyrosine hydroxylase in a subset of neurons.

    Finally, the use of the word “spreading” of pathology is misleading in the context of this experiment. When injecting PFFs into the striatum and monitoring aggregates in the substantia nigra, or loss of neurons in the nigra, one is only assessing the uptake and retrograde transport of α-synuclein assemblies that act as seeds for endogenous α-synuclein. To address “spreading” would require examining brain regions that are “one further synapse away.”

    View all comments by Patrik Brundin

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  1. Toxic α-Synuclein: Egged on by ApoE4, Thwarted by ApoE2?