New research from Northwestern Medicine has found that the immune system in the blood of patients with Alzheimer's it is epigenetically altered. This means that patients' behavior or environment has caused changes that affect how their genes work.
The study was published February 9 in Neuron.
Altered immune genes in patients diagnosed with Alzheimer's disease
Many of these altered immune genes are the same ones that increase an individual's risk of Alzheimer's. Northwestern scientists theorize that the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors.
“It is possible that these findings implicate the peripheral immune response in Alzheimer's disease risk,” said lead investigator David Gate, assistant professor of neurology at Northwestern University's Feinberg School of Medicine. “We still don't understand whether these changes reflect brain pathology or whether they precipitate the disease.”
Previous research has shown that many of the mutated genes that put a person at greater risk for Alzheimer's are found in the immune system. But scientists have primarily studied the brain's central immune system because Alzheimer's is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.
Gate decided to study blood. He and his colleagues found that each type of immune cell in Alzheimer's patients exhibits epigenetic changes, indicated by open chromatin. Chromatin is the packaging of DNA inside cells. When chromatin is open, or exposed, the cell's genome is vulnerable to alterations.
Then, Gate looked at which genes are most open in these immune cells. She found that one receptor, CXCR3, on T cells was more exposed. Gate believes that CXCR3 works like an antenna on T cells that allows cells to enter the brain. T cells normally do not enter the brain because they can cause inflammation.
“The brain is giving off a signal that it's damaged, and the T cells are homing in on that signal via their antenna, CXCR3,” Gate said.
“T cells can be very toxic in the brain, but we don't even know if these cells might be trying to repair the damage in the brain,” Gate said.
Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.
“Overall, these findings indicate that immune function in Alzheimer's patients is significantly impaired,” Gate said. “It could be that environmental factors, such as pollutants or infections that a person has throughout their life cause these epigenetic changes.”
The findings revealed several genes that could be therapeutic targets for manipulating the peripheral immune system. The next steps in research are preclinical studies using in vitro culture systems and animal models to test these targets.
Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova, and Lynn van Olst.
Researchers have revealed new links between Alzheimer's disease and the blood-brain barrier, finding connections between variants of a gene called EphA1 and the disease.
Genome-wide association studies have linked EphA1 gene variants to Alzheimer's disease, and one specific genetic variant, P460L, is associated with an increased risk of late-onset Alzheimer's disease.
Professor Ann Ager, from Cardiff University School of Medicine, said: “The EphA1 gene is known to play a role in the recruitment of immune cells. We hypothesized that the P460L variant might disrupt EphA1 activity and affect inflammation in the brain, leading to an increased risk of developing Alzheimer's disease.”
To investigate this, they used cellular models to study the activity of the P460L gene variant in T cells and endothelial cells of the blood-brain barrier.
Normally, EphA1 is involved in the immune response of T cells in the brain. They found that the P460L variant impacted the T cell immune response in the brain.
Helen Owens, Cardiff University School of Medicine, said: “We found that the P460L variant disrupts the normal behavior of EphA1 and impacts immune responses and blood vessels in the brain. Our study suggests that the P460L variant alters EphA1-dependent signaling which has implications for blood-brain barrier function in late-onset Alzheimer's disease.
“Future studies will focus on determining the role of the P460L variant in T cell biology to evaluate its impact on T cells and the blood-brain barrier. This work will help establish whether targeting P460L activity has therapeutic po
tential for the treatment of late-onset Alzheimer's disease.” illness in the future.”
Dutch scientists have discovered five biological variants of Alzheimer's disease, which may require different treatments. As a result, previously tested drugs may mistakenly appear to be ineffective or only minimally effective. This is the conclusion of researcher Betty Tijms and colleagues from Alzheimer Center Amsterdam, Amsterdam UMC and Maastricht University. Their study is published in Nature Aging.
In people with Alzheimer's disease, amyloid and tau proteins accumulate in the brain. In addition to these lumps, other biological processes such as inflammation and nerve cell growth are also involved. Using new techniques, the researchers were able to measure these other processes in the cerebrospinal fluid of patients with amyloid and tau clots.
Betty Tijms and Pieter Jelle Visser examined 1,058 proteins in the cerebrospinal fluid of 419 people with Alzheimer's disease. They found that five biological variants exist within this group. The first variant is characterized by increased production of amyloid. In a second type, the blood-brain barrier is disrupted, resulting in reduced amyloid production and less nerve cell growth.
In addition, the variants differ in the degree of protein synthesis, the functioning of the immune system, and the functioning of the organ that produces cerebrospinal fluid. Patients with different variants of Alzheimer's also showed differences in other aspects of the disease. For example, researchers found a more rapid course of the disease in some subgroups.
The findings are of great importance for drug research. They could mean that a certain drug might only work in a variant of Alzheimer's disease. For example, drugs that inhibit amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with reduced amyloid production. It is also possible that patients with one variant have a higher risk of side effects, whereas that risk would be much lower with other variants.
The next step for the research team will be to demonstrate that Alzheimer's variants actually react differently to drugs, in order to treat all patients with appropriate drugs in the future.
A further study by researchers at the University of Eastern Finland found that the APP A673T genetic variant, which protects against Alzheimer's disease, alters the levels of several proteins and peptides linked to beta-amyloid metabolism in human biofluids and models of cell cultures, including beta-amyloid yes. These new data support the idea that even a modest reduction in beta-amyloidogenic processing of APP may be a feasible strategy for the prevention of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia with over 40 million people affected worldwide. Two of the main pathological features of AD are amyloid plaques, composed of toxic beta-amyloid (Aβ) peptides, and neurofibrillary tangles, composed of hyperphosphorylated tau protein. Although these molecular features have been known for decades, there have been many obstacles in developing therapies for effective prevention or treatment of AD.
However, recent clinical trials targeting different phases of Aβ aggregation have shown promising results in slowing disease progression. Aβ is part of the amyloid precursor protein (APP) and is generated by sequential proteolytic cleavage of APP. In 2012, Icelandic researchers discovered a genetic variant within the APP gene that protects its carriers from AD.
Accordingly, a previous study conducted at the University of Eastern Finland found that carriers of the APP A673T variant show lower levels of Aβ in plasma compared to control individuals. Since the discovered APP A673T variant is very rare and found almost exclusively in Nordic populations, there are only few studies on its effects and mechanisms.
In the current study, published in Neurobiology of Disease, researchers analyzed the cerebrospinal fluid (CSF) and plasma of APP A673T carriers and screened the individuals using mass spectrometry-based proteomics, which allows identification of changes in protein levels between study groups in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with pathogenic APP mutations.
The study reports for the first time the protective effects of the APP A673T variant against AD-related alterations in cerebrospinal fluid, plasma and brain biopsy samples of carriers of the genetic variant. Cerebrospinal fluid levels of Aβ42 and soluble APP-beta (sAPPβ), which is another metabolite of beta-amyloidogenic processing of APP, were significantly decreased in APP A673T carriers compared to well-matched controls who did not carry the variant protective.
The unbiased proteomic approach of CSF and plasma samples from APP A673T carriers identified differences in the levels of several proteins and peptides that are intimately involved in protein phosphorylation, inflammation and mitochondrial function. Importantly, some of the identified key targets showed an inverse correlation in postmortem brain tissue of AD patients in relation to disease severity.
In 2D and 3D neuronal cell culture models expressing two strong AD-causing APP mutations, introduction of the APP A673T variant resulted in notable changes in APP processing pro
ducts. Consistent with the CSF findings, notably sAPPβ levels were lower in all models expressing APP A673T, often accompanied by reduced Aβ42 levels. These results demonstrate the efficacy of the protective APP variant A673T in shifting APP processing from the beta-amyloidogenic pathway towards the non-amyloidogenic pathway, even in the presence of two pathogenic APP mutations.
In summary, these findings highlight that even a modest reduction in beta-amyloidogenic processing of APP could be a feasible strategy for AD prevention. Furthermore, unbiased proteomic analyzes have highlighted specific targets and pathways, which may play a key role in AD progression.
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