07 Feb 2020
ApoE4s rap sheet just grew longer. Not only does ApoEs notorious allele accelerate A and tau pathology, it also drives the toxic aggregation of -synuclein, according to two studies published February 5 in Science Translational Medicine. One was led by Guojun Bu at the Mayo Clinic in Jacksonville, Florida; the other, by David Holtzman at Washington University in St. Louis. Both reported that ApoE4 aggravated -synuclein phosphorylation, worsened motor and memory problems, and ramped up neurodegeneration in different mouse models. Once again, the goody-two-shoes allele, ApoE2, was protective, Holtzman and colleagues reported. People with Lewy body dementia who inherited an ApoE4 allele had more phosphorylated -synuclein and faster cognitive decline than noncarriers.
Patrik Brundin of the Van Andel Research Institute in Grand Rapids, Michigan, said the studies further blur the line between Alzheimers and Lewy body dementias, in terms of both genetic risk and neuropathology. The findings suggest that there might be opportunities to develop [single] therapies that target more than one of these neurodegenerative disorders in the future, he wrote.
Dementia with Lewy bodies (DLB) and Parkinsons disease dementia (PDD) both fall under the umbrella of Lewy body dementias (LBDs), which hit patients with a double whammy of movement problems and cognitive impairment. Lewy bodies chock-full of aggregated -synuclein underlie these disorders, but many people with LBD also have A and tau pathology.
ApoE4, the strongest genetic risk factor for late-onset Alzheimers, also increases the risk for cognitive decline in people with PD, and is a risk factor for DLB as well (Mata et al., 2014;Dec 2015 news; Guerreiro et al., 2018). Studies hinted that in LBDs, ApoE4 works in much the same way as it does in AD, by ramping up A and/or tau pathology (Irwin et al., 2017; Sep 2016 news). However, others have reported that ApoE4 promotes -synuclein pathology independently (Tsuang et al., 2013;Dickson et al., 2018).
To directly assess this, researchers led by Bu used a mouse model of synucleinopathy. First author Na Zhao injected adeno-associated viruses expressing human -synuclein into both lateral ventricles of newborn ApoE-targeted replacement mice. These express human ApoE2, ApoE3, or ApoE4in place of the endogenous mouse gene.
Nine months later, the scientists used two antibodiesone that recognizes pathological conformations of -synuclein in people with LBD, and the other specific for -synuclein phosphorylated at serine-129to measure -synuclein pathology in multiple brain regions. They found roughly double the amount of both pathological conformers and phosphorylated -synuclein in several brain regions of Syn-ApoE4 compared with Syn-ApoE2 or Syn-ApoE3 mice. Immunoreactivity of the two antibodies correlated tightly.
This uptick in -synuclein pathology had consequences. All the Syn mice were unbalanced and uncoordinated compared with controls, but ApoE4 mice fared worst. They also spent more time in an exposed area, suggesting they had lost some of their normal fear and inhibition. While Syn-ApoE2 and Syn-ApoE3 mice readily remembered sounds that signaled an impending foot shock, Syn-ApoE4 mice had trouble on this memory task.
Normal neuron and synaptic protein levels in E2 and E3 mice stood in contrast to 10 percent fewer neurons in ApoE4s and a dip in levels of the postsynaptic protein PSD95. E4 mice had astrogliosis and microglial activation that were absent in Syn mice expressing the other alleles. However, the researchers found no correlation between the burden of pathological conformers of -synuclein in a given mouse and its degree of astrogliosis or microglial activation, suggesting the stepped-up neuroinflammation in ApoE4 mice was unrelated to the increased -synuclein pathology.
A transcriptomic analysis revealed lower expression of genes involved in lipid metabolism and less glycogen synthase activity in ApoE4 mice, as well as suppression of genes needed for synaptic signaling, protein metabolism, and social behavior.
Does ApoE4 influence -synuclein pathology in LBD? To find out, Zhao and colleagues measured pathologic conformations and p-Ser129 -synuclein in postmortem brain samples from 44 people who had had pure LBD with little to no A pathology. Half were ApoE4 carriers. On average, they had more p-Ser129 -synuclein than age-matched noncarriers, but not more of the pathological conformation. The researchers detected no differences in astrocytic or microglial markers between carriers and noncarriers, nor did glial activation markers correlate with the burden of p-Ser129 -synuclein across all participants. Together, these findings suggested that ApoE4 exacerbates -synuclein pathology in people with LBD but does not necessarily stoke neuroinflammation.
Bu said the lack of a direct link between the burden of -synuclein pathology and glial activation was unsurprising. As an intracellular protein, -synuclein is less likely to incite glial cells than extracellular aggregates, such as A.
Revving Up Syn. Postmortem brain samples of LBD patients indicate that ApoE4 carriers (bottom) had more phosphorylated -synuclein than did noncarriers. [Courtesy of Zhao et al., Science Translational Medicine, 2020.]
In the second paper, first author Albert Davis and colleagues used a different mouse. They crossed A53T-Syn transgenic mice with the same ApoE-targeted replacement mice Bu and colleagues used. Compared with the viral approach, the A53T-Syn mice develop more severe disease, becoming paralyzed by 12 months of age. While Bus injected mice had -synuclein pathology in many brain regions, the vast majority of -synuclein inclusions in the A53T-Syn mice developed in the brainstem, with sparse pathology in the neocortex.
Analyzing brainstem lysates from 12-month-old mice, Davis detected the highest levels of insoluble -synuclein, as well as p-Ser129 -synuclein, in ApoE4 mice. ApoE3 and ApoE knockouts had progressively less, and in lysates from ApoE2 mice, insoluble and phosphorylated forms of -synuclein were virtually undetectable. Immunohistochemistry of brainstem sections told a similar story, with ApoE2 mice having no detectable phosphorylated -synuclein, while ApoE4 had the most. Interestingly, p-Ser129 -synuclein only appeared in mice with end-stage paralysis, which afflicted many ApoE4 and ApoE knockout mice by 12 months of age. ApoE2 mice did not develop severe paralysis until much later, around 18 months, suggesting that the allele staved off both -synuclein pathology and neurodegeneration.
The scientists also compared transcriptomes. Both the amount of -synuclein pathology and end-stage paralysis tracked with higher expression of proinflammatory genes, but not with ApoE genotype alone. This suggested that neuroinflammation arose in response to -synuclein pathology and neurodegeneration, as opposed to being caused by ApoE4. Davis also picked up modules of myelination and anti-apoptotic genesthese were more highly expressed in ApoE2 mice.
Compared with Bus study, Davis found stronger ties between the burden of -synuclein pathology and neuroinflammation. The reason for this discrepancy is unclear, but both researchers believe it could come down to differences between mouse models. Because the A53T-Syn mice express much higher levels of -synuclein than the virally infected model, the former could evoke a more pro-inflammatory component, Bu suggested.
ApoE Impacts Syn. Brainstem sections reveal the most p-Ser129 -synuclein pathology (red) and astrogliosis (green) in ApoE4 mice; ApoE2 mice had neither. [Courtesy of Davis et al., Science Translational Medicine, 2020.]
Davis next investigated the relationship between ApoE genotype and cognition in several cohorts of PD patients. Among 251 people with PD in the Parkinsons Progression Markers Initiative, the researchers found faster decline on the Montreal Cognitive Assessment in the ApoE4 carriers. While people with abnormal CSF A42 or p-tau also declined faster on this screen, ApoE4 correlated independently. In two other PD cohorts, the researchers found ApoE4 carriers declined more sharply on the mini-mental state examination.
While the two papers came to slightly different conclusions in some respects, their main conclusion was the same, Bu said: ApoE4 can drive -synuclein pathology in the complete absence of amyloid.
Exactly how ApoE does that remains unclear. ApoE is an extracellular protein, whereas the vast majority of -synuclein resides inside, attached to synaptic vesicles. Still, small pools of -synuclein have been detected outside of cells and, when aggregated, it can spread between neurons via a templated misfolding mechanism, at least in mice. It is possible the two lipophilic proteins meet up in this extracellular milieu, Bu said. In support of this, Davis also reported that preformed fibrils of -synuclein injected into the mouse striatum spread more readily into neighboring substantia nigra when the animals expressed ApoE4.
Thomas Montine of Stanford University favors the idea that ApoE isoforms sway -synuclein aggregation indirectly, via their role as immune modulators. He noted that, in general, ApoE4 promotes pro-inflammatory responses, while ApoE2 does the opposite.
If ApoE4 drives -synuclein aggregation, then why is it a risk factor for LBD, but not PD? Davis said the answer could come down to where in the brain ApoE4 influences -synuclein aggregation. Perhaps the allele is most impactful in cortical and limbic regions involved in cognition, he speculated. These regions are more affected by -synuclein pathology in LBD than in PD, in which -synuclein aggregates primarily pop up in the midbrain. Davis plans to use mouse models with more widespread -synuclein aggregation to investigate this. Montine concurs that neuropathological studies suggest that ApoE4 strongly affects -synuclein aggregation in cortical and limbic regions (Dickson et al., 2018). Another possibility is that ApoE4 promotes the propagation of -synuclein pathology from the midbrain into these areas, Davis said.
Despite myriad unknowns, the new findings cast ApoE as a potential therapeutic target not only in AD, but also in LBD, Bu and Davis agreed. Montine noted that the protective effect of ApoE2 reported in Daviss study is important, especially in light of recent reports that the allele strongly protects against AD (Feb 2020 news). A therapy that mimics the behavior of ApoE2 could benefit patients with LBD and AD, he said.Jessica Shugart
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Toxic -Synuclein: Egged on by ApoE4, Thwarted by ApoE2? - Alzforum
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