Mouse Study: 4 Approved Meds Are Potential Alzheimer’s Treatments

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by Steve Bryson, PhD |

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Detailed molecular signatures in three mouse models of Alzheimer’s disease at different disease stages allowed for identification of four approved medicines that may be potential Alzheimer’s treatments, a study revealed.

The four medications that demonstrated efficiency are now used to treat hypertension (high blood pressure) and inflammation in humans.

The study, “Identification and drug-induced reversion of molecular signatures of Alzheimer’s disease onset and progression in AppNL-G-F, AppNL-F, and 3xTg-AD mouse models,” was published in the journal Genome Medicine.

The main hallmarks of Alzheimer’s disease are the buildup and clumping of amyloid-beta protein in the form of plaques, and the formation of Tau neurofibrillary tangles. This process leads to nerve cell death in the hippocampus, an area of the brain associated with learning and memory.

Despite current evidence of the molecular bases of Alzheimer’s disease, understanding of disease onset and progression is incomplete. Furthermore, therapies that target a single biological process have yet to yield desired outcomes.

That’s why a more systemic approach to treatment might help advance effective therapeutics, especially in the early stages of the disease before irreversible brain damage occurs.

To gain an understanding of Alzheimer’s disease progression, scientists based at the Institute for Research in Biomedicine (IRB) in Barcelona, Spain, characterized three different Alzheimer’s mouse models at three stages of the disease — early, intermediate and advanced.

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Based on the resulting Alzheimer’s-related molecular signatures, the team also searched for known medicines that may reverse these signatures.

Two standard mouse models — AppNL-F and AppNL-G-F — were used that carried mutations in the App gene, which gives rise to the amyloid precursor protein (APP) and is associated with inherited disease in humans. The third model — 3xTg-AD — was bred to overproduce human APP and Tau proteins, both associated with the development of Alzheimer’s disease.

Three different disease stages were mimicked with 3-, 9-, and 18-month-old AppNL-F mice, 3-, 6-, and 9-month-old AppNL-G-F mice, and 3-, 8-, and 15-month-old 3xTg-AD mice.

First, the cognitive status of AppNL-F and AppNL-G-F mice at different disease stages was assessed using the novel object recognition (NOR) test, in which healthy mice typically spend more time investigating a novel object over a familiar object.

Memory defects were found only in older AppNL-F mice. In contrast, younger AppNL-G-F mice could not discriminate the novel object, “indicating earlier cognitive impairment,” in this model, the team wrote.

Consistently, the presence of amyloid-beta plaques in the hippocampus was found only in older AppNL-F mice, but all ages of AppNL-G-F mice showed amyloid-beta plaques. The 3xTg-AD mice showed cognitive impairment and the presence of amyloid-beta plaques at 8- and 15 months, reflecting intermediate onset.

Gene expression and protein levels were then measured in the hippocampus of all Alzheimer’s mice and compared to healthy mice. Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Consistent with memory tests, young AppNL-G-F mice showed the most prominent effects on gene expression and protein production, indicating that “most of the changes take place between 3 and 6 months of age, when [amyloid-beta] plaques became more evident and cognitive impairment appeared,” the researchers wrote.

Common molecular patterns

Notably, there was a significant overlap between the more active (upregulated) genes and proteins in the three different mouse models, “suggesting that, despite the notable differences between models, there are common molecular patterns across them,” they added.

A comparison of healthy aging and Alzheimer’s progression showed an increase in the activity of genes associated with the inflammatory process, which is known. However, a significant number of these genes also were upregulated in younger AppNL-G-F animals, suggesting that amyloid-beta disease promoted features of molecular aging.

“What we have observed is that, although Alzheimer’s disease shares some features of accelerated ageing, it is also affected by totally different ageing processes,” study lead Patrick Aloy, PhD, said in a press release.

Gene expression at different ages of mice was measured to identify molecular signatures across disease progression. Alzheimer’s-related signatures in AppNL-F and AppNL-G-F mice followed similar trends in the comparisons of 3- vs. 15-month and 8- vs. 15-month 3xTg-AD mice, “indicating that these signatures are common to the three AD [Alzheimer’s disease] models,” the scientists wrote.

One of the most upregulated genes in the Alzheimer’s signature was GFAP, which also was increased at the protein level and previously shown to accumulate in the brains of patients.

In contrast, reduced gene expression (downregulation) signatures were related to defects in signaling between nerve cells and may “reflect the cognitive impairment observed in the AppNL-G-F mice at 6 and 9 months of age, [and] reverting some of these molecular changes could offer therapeutic opportunities,” they added.

Next, levels of protein were compared between models at different ages to healthy mice. Changes at the protein levels strongly correlated with their gene expression across all three models. Conversely, this correlation was much weaker in older mice, in which the clumping of proteins was uncoupled 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 removal,” Aloy said.

Finally, the team sought to identify small molecules that could “revert” the gene expression signatures found in these Alzheimer’s mice using a tool called Chemical Checker.

Among 8,250 candidate compounds, 125 highly ranked non-steroidal anti-inflammatory drugs (NSAIDs) were identified, which are among the most common medications, typically prescribed as anti-inflammatories, pain relievers, and to reduce fever.

“Epidemiological studies already indicated that people who regularly take anti-inflammatories show a lower incidence of Alzheimer’s disease, but this had not been correlated with a specific medication or mechanism,” said Aloy.

The list also included a number of approved agents to treat high blood pressure (hypertension). The effectiveness of selected compounds was tested in 5-month-old AppNL-G-F mice because it showed cognitive impairment at early stages.

Two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives  (penbutolol and bendroflumethiazide) were found to prevent cognitive impairment based on the novel object recognition test. Further analysis found these compounds reduced amyloid-beta plaques in the hippocampus and partially restored Alzheimer’s-related molecular signature genes.

“The characterization of three [Alzheimer’s disease] mouse models at different disease stages has provided an unprecedented view of [Alzheimer’s disease processes] and how this differs from physiological ageing,” the authors concluded. “Moreover, our computational strategy to chemically revert [Alzheimer’s disease] signatures has shown that, despite the inconclusive and contradictory results reported, NSAID and anti-hypertensive drugs may still have an opportunity as anti-[Alzheimer’s disease] agents.”

“The results that we are publishing are most promising, and we hope that further research can be done on them because they could give rise to a paradigm shift in the treatment of this disease,” Aloy said.