Neurogenetic contributions to amyloid beta and tau spreading in the human cortex

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Abstract

Tau and beta-amyloid (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease (AD). Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau PET imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau- and Aβ-propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as “axon-related” and the Aβ profile as “dendrite-related”. This is the first study revealing distinct genetic profiles that may confer vulnerability to tau- and Aβ- in-vivo-propagation in the human brain.

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Yang Shi, Shane Liddelow, Scott T. Smith … (2017)

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

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Resting-state functional connectivity in neuropsychiatric disorders.

Michael D. Greicius (2008)

This review considers recent advances in the application of resting-state functional magnetic resonance imaging to the study of neuropsychiatric disorders. Resting-state functional magnetic resonance imaging is a relatively novel technique that has several potential advantages over task-activation functional magnetic resonance imaging in terms of its clinical applicability. A number of research groups have begun to investigate the use of resting-state functional magnetic resonance imaging in a variety of neuropsychiatric disorders including Alzheimer's disease, depression, and schizophrenia. Although preliminary results have been fairly consistent in some disorders (for example, Alzheimer's disease) they have been less reproducible in others (schizophrenia). Resting-state connectivity has been shown to correlate with behavioral performance and emotional measures. It's potential as a biomarker of disease and an early objective marker of treatment response is genuine but still to be realized. Resting-state functional magnetic resonance imaging has made some strides in the clinical realm but significant advances are required before it can be used in a meaningful way at the single-patient level.