Alzheimer’s disease treatment research has largely focused on preventing the buildup of amyloid beta protein plaques in the brain, which are distinctive features of the disease. Now, researchers have developed a new vaccine using a mouse model, which targets a different protein found in aging brain cells and blood vessels.
The origins of the amyloid beta model and its use as a treatment target have been controversial in recent years. For example, when the Food and Drug Administration (FDA) granted accelerated approval for the use of lecanemab (Leqembi) in treating people with early Alzheimer’s disease in January 2023, controversy was raised over its efficacy and side effects. Particularly when, later that month the FDA did not approve pharmaceutical company Eli Lilly’s Alzheimer’s drug donanemab, as expected, as more data was needed to determine efficacy.
In July 2022, controversy over the development of drug treatments for Alzheimer’s disease peaked following an investigation published in Science in July 2022 that alleged some images had been manipulated in the highly influential paper published in Nature in 2006 that were considered to have confirmed the amyloid beta-hypothesis.
This explosive year for Alzheimer’s science was perhaps not surprising when considering that finding a drug target for Alzheimer’s disease is potentially big business for pharmaceutical companies. There are currently 6 million cases in the United States alone, expected to rise to 13 million by 2050, and that is a lot of potential patients.
Dr. Santosh Kesari, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, told Medical News Today in an email:
“All of the currently approved drugs (memantine, donepezil, etc) for Alzheimer’s treat the symptoms, such as improving memory or mood but do not change the disease course.For the past three decades scientists have tried to develop drugs that target the amyloid protein which is a hallmark feature of the disease. For the first time, an antibody drug (lecanemab) is now fully approved for Alzheimer’s disease in its earliest stages by targeting the amyloid protein which is thought to be the underlying cause of the disease.”
There are other mechanisms thought to underlie Alzheimer’s disease progression, including inflammation. Inflammation also underpins other conditions, such as atherosclerosis, and there has been some debate over whether or not the two conditions are linked. Both diseases involve inflammation and vasculature. Certain APOE gene variants are known to predispose individuals to both diseases.
The search for a drug that could target both diseases has been in development in mouse models for around a decade.
One recent example has been the work of researchers in Tokyo who determined that senescence-associated glycoprotein (SAGP-protein) was upregulated in immune and vascular endothelial cells in mouse models with atherosclerosis. Increased expression of this protein has been linked to increased risk of atherosclerosis and Alzheimer’s disease in mouse models with variants on the APOE gene. SAGP-protein is also found around the microglia, the brain’s immune cells.
Previous experiments by the team have shown that downregulation of the expression of this protein leads to a decrease in atherosclerotic plaques in the aorta of mice with variants on the APOE gene, and improved the glucose metabolism of obese mice.
Alongside these findings, they revealed they had developed a vaccine that targeted older cells with a high level of SAGP-protein expression.
The same team recently announced they had discovered this vaccine could also improve the behavior of mouse models of Alzheimer’s disease, decrease levels of amyloid-beta peptide (the precursor to amyloid beta-protein), as well as lower levels of inflammatory molecules.
These results from preliminary research were presented at the American Heart Association’s Basic Cardiovascular Sciences Scientific Sessions 2023 in Boston.
Lead author Dr. Chieh-Lun Hsiao told MNT in an email: “Unfortunately, how we generate vaccine is not allowed to expose, but the design of the vaccine is to eliminate or reduce the cells which contain an abundance of our target, SAGP.”
When asked how the vaccine works, Dr. Hsiao explained:
“Vaccination is a kind of training for the immune system to recognize a specific outsider, an antigen, or a peptide. We would say, in our theory, we hypothesize that the cells with SAGP-high expression are pathogenic/abnormal. Therefore, individuals after vaccination would have the immunity that is possible to recognize SAGP-HIGH expressed signal, and remove/destroy the cells which contains SAGP-HIGH expressed signal afterwards.”
The authors of the study concluded that their vaccine could potentially be used to treat Alzheimer’s disease.
Researcher Dr. Hsiao said: “In the future, we’d probably shift to other animal models for further examination of vaccine efficacy. Also, we are interested in phenotype change among cell types after vaccination. We’ll focus more on the mechanisms in our next steps.”
Kath Intson, CEO of precision medicine startup Varient and a Ph.D. candidate at the University of Toronto in Canada, who was not involved in the research, said there needed to be more information about the potential side effects of this target.
Intson told MNT in an email:
“The probability of a medicine like this being administered prophylactically – i.e., like a vaccine – to prevent AD is modest at best. For one, the target is microglia, the brain’s equivalent to immune cells. I would be curious to know more about the proportion of microglia that are highly enriched in SAGP that were eliminated. As you can imagine, there are consequences to removing a large population of the brain’s immune system.”
She also questioned targeting the buildup of amyloid-beta peptide (APP), the precursor to amyloid beta-protein, for treating Alzheimer’s disease: “One note – we must stop thinking of APP accumulation as an inherently pathological physiological process.
“Previous studies have demonstrated that APP plays a protective role in the brain following acute injuries, such as stroke or traumatic brain injury. In brief, APP upregulation promotes brain cell survival in the short term in response to these insults. I would be very cautious of any proposal of vaccines rolled out to the general population with APP-elimination targets. To remove this vital and normal function from healthy patients, would have implications for their health concerning other brain-damaging conditions.”
This article originally appeared here and was republished with permission.