Apolipoprotein E protein isoforms, particularly ApoE4, appear to accelerate brain-wide tau propagation that eventually leads to neuronal injury and death in a manner independent from amyloid-beta, according to findings from transgenic mouse model studies.

“We found ApoE itself, especially ApoE4, was essential to neuronal death,” wrote first author Yang Shi of Washington University, St. Louis, and her colleagues, led by David M. Holtzman, MD , in new research published in Nature. “With pathological tau accumulation, the presence of ApoE, especially ApoE4, may make neurons more susceptible to degeneration, whereas the absence of ApoE may protect neurons from death.”

The new research also illustrates a differential effect between the three APOE alleles. In the team’s in vivo study, tau-expressing mice with the APOE4 allele were most affected, and those with the E3 and E2 versions progressively less so. Mice that didn’t express the human gene at all showed no change in tau and no immune reaction ( Nature. 2017;549:523-7 ).

This new picture of tauopathy – a common feature in Alzheimer’s, frontotemporal dementia, corticobasal degeneration, Pick disease, and progressive supranuclear palsy – suggests an expanded role for ApoE, which until now has been associated mostly with increased amyloid deposition in the Alzheimer’s disease (AD) brain.

While the results clearly need to be confirmed by other labs, the experiment could identify new targets in AD research, said Michael S. Wolfe, PhD , the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“I think this paper is potentially very important, identifying what appear to be strong connections between tau and ApoE that we had no idea about before,” Dr. Wolfe said in an email. “While independent confirmation is needed, this new work is coming from a strong research team that has made other seminal discoveries in the field. Uncovering the molecular basis for ApoE’s effect on tau pathology and glial cell activation may suggest new targets for drug discovery for AD.”

Evidence of ApoE4’s greater impact

To examine ApoE’s effect on tau, the research team bred new lines of genetically modified mice, all of which expressed human tau. Some also expressed human ApoE4, E3, or E2 in place of mouse ApoE. A comparator mouse expressed tau, but not ApoE.

By the time the mice were 9 months old, the tau-E4 strain showed significantly more brain atrophy than did the tau-E3 and tau-E2 strains. The mice who expressed tau but were free of ApoE showed no brain changes.

A closer look showed that atrophy occurred primarily in areas associated with the cognitive changes seen in dementia: the hippocampus, piriform/entorhinal cortex, and amygdala. The ventricles were also enlarged.

“These results revealed an important role of ApoE in regulating tau-mediated neurodegeneration, with ApoE4 causing more severe damage and the absence of ApoE being protective,” the investigators wrote.

The E4/tau tango started early, too, the team noted. At 3 months old, tau-E4 mice had no obvious brain atrophy, but already had significantly more soluble tau than did any of the other strains. By 9 months, when tauopathy was obvious, the tau-E4 mice still had more of the protein, which had shifted from a soluble to an insoluble and hyperphosphorylated state. The tau-E4 mice didn’t appear to be making more tau than the others, though; rather, they were less able to clear it through the neurons’ clearing and recycling system of autophagy.

Drilling down further into the neurons’ pathophysiology, the team found that tau first appeared in the axons of dentate gyrus granule cells in the hippocampus, and then, at an early age, moved into the cell body. Again, there were APOE allele–specific patterns to tau propagation. The team saw four major tau staining patterns, which correlated with the level of brain atrophy. Types 1 and 2, associated with least atrophy, occurred most often in the tau-only, ApoE-negative mice; type 4, associated with the greatest atrophy, occurred most often in the tau-E4 mice.

“The featured distribution of these … patterns, which either represent different tau structures or progressively more advanced pathological tau stages, indicate ApoE affects either tau conformation or tau pathology progression,” the investigators wrote.

Greatest neurodegeneration seen with ApoE4

Tau-mediated neurodegeneration initiated levels of inflammatory response that also depended on the type of ApoE isoform. Exposure to a culture of damaged neurons and mixed glial cells caused microglia to release a flood of inflammatory cytokines that called in a host of astrocytes to kill damaged tau-E4 neurons en masse, but attacked the tau-E3, tau-E2, and tau-only strains much less. This finding indicates that “ApoE itself was directly involved in inducing neurotoxicity in tau-expressing susceptible neurons,” the team wrote.

Finally, they investigated this model of neurodegeneration in postmortem brain samples of patients with corticobasal degeneration, Pick disease, and progressive supranuclear palsy – the three most common sporadic primary tauopathies. Patients with the E4 allele showed more severe neurodegeneration and a greater interaction of tau pathology and neurodegeneration. Amyloid deposition was associated with less severe neurodegeneration.

Taken together, the findings strongly suggest that the high-risk APOE4 allele is the linchpin that links neuroinflammation to neuronal death in the setting of tau pathology, the investigators concluded.

“The presence of degenerating neurons appeared to further induce neuroinflammation, which was augmented by ApoE4 owing to its inherently higher innate immune reactivity. While activated microglia may be protective to some extent in the setting of amyloid-beta pathology, by targeting plaques and reducing dystrophic neurites, they could be deleterious in tauopathy by directly targeting injured neurons and by activating toxic astrocytes. Enhanced neuroinflammation associated with ApoE4 may further exacerbate neurodegeneration.”

The study was funded by grants awarded to multiple investigators by the National Institutes of Health, the JPB Foundation, Cure Alzheimer’s Fund, AstraZeneca, the Consortium for Frontotemporal Dementia Research, the Tau Consortium, the National Multiple Sclerosis Society, the Nancy Davis Foundation, and the Amyotrophic Lateral Sclerosis Association. Dr. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics. He consults for Genentech, AbbVie, Eli Lilly, Proclara, GlaxoSmithKline, and Denali. Dr. Holtzman’s lab is funded by institutional research grants from C2N Diagnostics, Eli Lilly, AbbVie, and Denali.

On Twitter @Alz_Gal


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