Tau Alzheimers Research Paper

A new study is changing how scientists think about Alzheimer’s disease

By Emily Underwood

How does ApoE4 do its dirty work? Since 1993, when this variant of the apolipoprotein E gene was found to multiply the risk of the most common form of Alzheimer's disease as much as fourfold, researchers have probed its connections to β-amyloid, the dominant suspect for the cause of the illness. This protein fragment forms extracellular "plaques" that can disrupt brain signals and kill neurons. This week, however, one of the main proponents of the hypothesis that ApoE4 exacerbates amyloid pathology stunned many of his colleagues by showing that its most toxic effects may result from a damaging immune response to a different protein: tau.

"This is a seminal study" and has "profound clinical implications," says Bob Vassar, a molecular biologist at Northwestern University in Chicago, Illinois. The study also shifts the terms of an old debate over whether Alzheimer's treatments should focus on tau or amyloid, by suggesting both could be targeted through ApoE4. Because David Holtzman, the leader of the new study, has long championed a link between ApoE4 and β-amyloid, "it's very compelling to hear him argue now" that tau is central to ApoE4's dangerous influence, says Scott Small, a neuroscientist at Columbia University.

People with Alzheimer's disease die with brains riddled by both amyloid plaques and intracellular tau "tangles." Yet the evidence linking tau to ApoE4 has been indirect and circumstantial, says Holtzman, a neuroscientist at the Washington University School of Medicine in St. Louis in Missouri. In any case, scientists doubted that tau—normally a stabilizing protein within cells—could escape from neurons to interact with the cholesterol-ferrying protein made by ApoE, he says.

That turned out to be wrong. "When we learned that some tau actually escapes cells and that pathological forms can spread from to cell to cell, we thought maybe it is tenable to retest this."

For the new study, published today in Nature, Holtzman and colleagues took genetically engineered mice that produce a version of tau found in the brains of people with a neurodegenerative disease similar to Alzheimer's, and cross-bred them with strains expressing ApoE4 or the two other main human variants of ApoE: E2 and E3. They also crossed the tau mice with mice in which its ApoE had been disabled. When the team examined brain tissue in the four resulting strains, all the mice carrying the human variants of ApoE had tau tangles and neurodegeneration, with the most profound tissue loss in E4 mice. In the taumaking mice with no ApoE gene, however, there was little or no neuronal death.

That result alone "provides definitive evidence" that ApoE plays a major role in tau pathology, says Gary Landreth, a neuroscientist at Indiana University in Indianapolis.

Equally compelling, he and others say, was what happened when Holtzman's team took microglia and astrocytes—the brain's immune cells—from mice that express human ApoE4 and grew them in culture with neurons that contain the human tau. The immune cells launched an inflammatory response that appeared to kill neurons en masse. "This is a brand-new mechanism by which ApoE influences both Alzheimer's and other tauopathies, by affecting the innate immune response," Holtzman says.

Holtzman and others now believe that β-amyloid plays an important role in triggering the onset of Alzheimer's disease, with tau deposits creating later damage. "Gone are the days when we had these competing camps" of tau versus amyloid, says Dennis Selkoe, a neurologist at Harvard Medical School in Boston and an architect of the amyloid hypothesis. "It's both—a double whammy." But, he adds, the study reveals an important new target for treatments: the destructive conspiracy of pathogenic tau and ApoE4.


Emily Underwood

Emily is a contributing correspondent for Science, covering neuroscience.

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Alzheimer’s disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer’s disease, neuropathology and atrophy preferentially affect ‘hub’ brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer’s disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer’s disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer’s disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker ‘small-world’ properties. Conversely, in PSP, unlike in Alzheimer’s disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer’s disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

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