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APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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Fluke Discovery Finds Mature Mouse Neurons Can Be Reprogrammed, Researchers Report

mature neurons

While attempting to transform a type of brain cell into neurons, researchers instead discovered they can turn mature neurons — which were previously believed to be unchangeable — into neurons that produce dopamine, the neurotransmitter that is lost in Parkinson’s disease.

The incidental discovery has therapeutic implications for Parkinson’s and other neurological conditions, according to the team at the  University of Texas Southwestern Medical Center that made the finding.

“To find that we could manipulate neurons to change their identity in adulthood was truly unexpected,” Chun-Li Zhang, PhD, a professor of molecular biology at UT Southwestern, said in a press release.

Zhang and his team published their study, “Phenotypic Reprogramming of Striatal Neurons into Dopaminergic Neuron-like Cells in the Adult Mouse Brain,” in Stem Cell Reports

The brain is made up of different types of cells. The most abundant of these are glial cells, which support and protect neuronal cells. They are more reactive and proliferative than neurons.

Research has shown that glial cells can be turned into neurons and form synaptic connections — specialized neuronal structures that allow neurons to communicate with each other.

So the UT Southwestern researchers set out to transform glial cells into neurons that could produce dopamine — the substance that is lost in Parkinson’s patients and that is involved in reward behavior — by using a mix of genetic factors and a chemical compound directly injected into mouse brains.

Using a viral vector, they injected the genetic factors into the striatum, a region rich in GABA-producing neurons that helps control motor skills. Dopaminergic neurons aren’t usually located in this region, but have long extensions that control neurons in the striatum, according to the researchers.

What they found, however, was that instead of converting glial cells, they converted the mature GABA-producing neurons into dopaminergic neurons.

“We got the new cells we wanted. But, they did not originate from glial cells,” Zhang said. “Rather than originating from glia, the new dopamine cells came from local, existing mature neurons without passing through a stem cell state. This is a mature cell-to-mature cell transformation.”

The new cells retained some of the characteristics of the original cells but resemble dopaminergic neurons more closely than inhibitory neurons. The researchers now aim to fully characterize these cells in future studies.

“We were amazed. To our knowledge, changing the identity of resident and mature neurons had never been accomplished,” Zhang said.

Reprogramming adult neurons from one type into another without going through a stem cell fate was previously not thought possible. Knowing now that it can be done provides a possible therapeutic strategy for neurological diseases.

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