Detailed molecular signatures in three mouse models of Alzheimer’s disease at different stages of the disease have identified four approved drugs that could be potential treatments for Alzheimer’s disease, a study found.
The four drugs that have been shown to work are now used to treat hypertension (high blood pressure) and inflammation in humans.
The study, “Identification and drug reversal of the molecular signatures of the onset and progression of Alzheimer’s disease in the AppNL-GF, AppNL-F and 3xTg-AD mouse models, ”Was published in the journal Genome medicine.
The main features of Alzheimer’s disease are the accumulation and agglutination of beta-amyloid protein in the form of plaques and the formation of Tau neurofibrillary tangles. This process leads to the death of nerve cells in the hippocampus, an area of the brain associated with learning and memory.
Despite current evidence for the molecular basis of Alzheimer’s disease, understanding of the onset and progression of the disease is incomplete. In addition, therapies that target a single biological process have not yet yielded the desired results.
That’s why a more systems approach to treatment could help advance effective therapies, especially in the early stages of the disease, before irreversible brain damage occurs.
To better understand the progression of Alzheimer’s disease, scientists at the Biomedicine Research Institute (IRB) in Barcelona, Spain, characterized three different mouse models of Alzheimer’s at three stages of the disease: early, intermediate and advanced.
Based on the resulting molecular signatures of Alzheimer’s disease, the team also looked for known drugs that could reverse these signatures.
Two standard mouse models – AppNL-F and AppNL-GF – were used which carried mutations in the Application gene, which gives rise to the amyloid precursor protein (APP) and is associated with an inherited disease in humans. The third model – 3xTg-AD – was created to overproduce human APP and Tau proteins, both associated with the development of Alzheimer’s disease.
Three different stages of the disease were mimicked with AppNL-F mice at 3, 9 and 18 months, AppNL-GF mice at 3, 6 and 9 months, and AppNL-GF mice at 3, 8 and 15 months. – 3xTg-AD mice one month old.
First, the cognitive state of AppNL-F and AppNL-GF mice at different stages of the disease was assessed using the Novel Object Recognition (NOR) test, in which healthy mice typically spend more time. to study a new object than a familiar object.
Memory defects were only found in older AppNL-F mice. In contrast, the younger AppNL-GF mice were unable to discriminate the new object, “indicating previous cognitive impairment,” in this model, the team wrote.
Consistently, the presence of beta-amyloid plaques in the hippocampus was only found in older AppNL-F mice, but all ages of AppNL-GF mice exhibited beta-amyloid plaques. The 3xTg-AD mice showed cognitive impairment and the presence of beta-amyloid plaques at 8 and 15 months, reflecting an intermediate onset.
Gene expression and protein levels were then measured in the hippocampus of all mice with Alzheimer’s disease and compared to healthy mice. Note that gene expression is the process by which the information contained in a gene is synthesized to create a functional product, such as a protein.
Consistent with memory tests, young AppNL-GF mice showed the greatest effects on gene expression and protein production, indicating that “most of the changes take place between 3 and 6 months old, when [amyloid-beta] the plaques became more evident and cognitive impairment appeared, ”the researchers wrote.
Common molecular models
Notably, there was a significant overlap between the most active (overregulated) genes and proteins in the three different mouse models, “suggesting that, despite the notable differences between the models, there are common molecular models between them,” they added.
A comparison of healthy aging and the progression of Alzheimer’s disease showed an increase in the activity of genes associated with the inflammatory process, which is known. However, a significant number of these genes were also upregulated in younger AppNL-GF animals, suggesting that beta-amyloid disease promoted features of molecular aging.
“What we have observed is that although Alzheimer’s disease shares some characteristics of accelerated aging, it is also affected by totally different aging processes,” said study director Patrick Aloy, PhD, in a press release.
Expression of genes at different ages of mice was measured to identify molecular signatures throughout disease progression. The Alzheimer’s disease-related signatures in AppNL-F and AppNL-GF mice followed similar trends in comparisons of 3xTg-AD mice at 3 vs. 15 months and 8 vs. 15 months, “indicating that these signatures are common to the three UN D [Alzheimer’s disease] models, ”the scientists wrote.
One of the most upregulated genes in Alzheimer’s disease signature was GFAP, which has also been increased in protein and has already been shown to accumulate in the brains of patients.
In contrast, the reduced gene expression signatures (downregulation) were linked to signaling defects between nerve cells and may “reflect the cognitive impairments observed in AppNL-GF mice at 6 and 9 months,” [and] reversing some of these molecular changes could offer therapeutic opportunities, ”they added.
Next, protein levels were compared between models at different ages and healthy mice. Changes in proteins were strongly correlated with their gene expression in all three models. Conversely, this correlation was much weaker in older mice, in which protein agglutination was decoupled from gene activity.
“This disease is caused by the abnormal accumulation of certain proteins, and we have seen that in some cases this is not caused by overproduction but by an error in their elimination,” said Aloy.
Finally, the team set out to identify small molecules that could “reverse” the gene expression signatures found in these mice with Alzheimer’s disease using a tool called the Chemical Checker.
Among the 8,250 candidate compounds, 125 high-level nonsteroidal anti-inflammatory drugs (NSAIDs) have been identified, which are among the most common drugs, usually prescribed as anti-inflammatory drugs, pain relievers and to reduce fever.
“Epidemiological studies have previously indicated that people who take anti-inflammatory drugs regularly have a lower incidence of Alzheimer’s disease, but this has not been correlated with a specific drug or mechanism,” Aloy said.
The list also included a number of agents approved to treat high blood pressure (hypertension). The efficacy of the selected compounds was tested on AppNL-GF mice aged 5 months, as they exhibited cognitive impairment at an early stage.
Two NSAIDs (dexketoprofen and etodolac) and two antihypertensive drugs (penbutolol and bendroflumethiazide) were able to prevent cognitive impairment based on the new object recognition test. Further analysis revealed that these compounds reduced beta-amyloid plaques in the hippocampus and partially restored molecular signature genes linked to Alzheimer’s disease.
“The characterization of three [Alzheimer’s disease] mouse models at different stages of the disease provided an unprecedented view of [Alzheimer’s disease processes] and how it differs from physiological aging, ”the authors concluded. “In addition, our calculation strategy to chemically reverse [Alzheimer’s disease] signatures showed that, despite the inconclusive and contradictory results reported, NSAIDs and antihypertensive drugs may still have an opportunity as anti-[Alzheimer’s disease] agents. “
“The results we are publishing are most promising, and we hope that further research can be done on them as they could lead to a paradigm shift in the treatment of this disease,” said Aloy.