Protein-targeting vaccine signposts Alzheimer’s breakthrough

Novel vaccine reduces amyloid plaques and may hold key to preventing or reducing the impact of Alzheimer’s disease.

A novel vaccine that targets inflamed brain cells associated with Alzheimer’s disease may hold the key to potentially preventing or modifying the course of the disease, according to preliminary research presented at the American Heart Association’s Basic Cardiovascular Sciences Scientific Sessions 2023.

Longevity.Technology: Approximately 3.7 million Americans, aged 30 years and older, had Alzheimer’s disease in 2017, and this number is projected to increase to 9.3 million by 2060 [1]. This pernicious form of dementia is one of the world’s most serious unmet health needs, and while there are treatments that may change disease progression, and therapies that can help ameliorate symptoms, there is still no definitive cure.

When cells enter a senescent state, they excrete a pro-inflammatory secretory phenotype that contributes to various aging-associated disorders. Previous research identified a novel protein, senescence-associated glycoprotein (SAGP), which functions as a biomarker of cellular senescence. Researchers also found that elimination of senescent cells targeting SAGP reduced aging-associated disorders such as atherosclerosis, diabetes and frailty [2].

Researchers at Juntendo University Graduate School of Medicine in Tokyo, Japan developed a vaccine to eliminate senescent cells that expressed SAGP – in effect, they developed a senolytic vaccine that was able to improve various age-related diseases including atherosclerosis and Type 2 diabetes in mice [3]. Another study also found that SAGPs are highly expressed in glial cells in people with Alzheimer’s disease, and based on the findings from these studies, the researchers tested their vaccine in mice to target SAGP-overexpressed cells to treat Alzheimer’s disease.

“Alzheimer’s disease now accounts for 50% to 70% of dementia patients worldwide. Our study’s novel vaccine test in mice points to a potential way to prevent or modify the disease. The future challenge will be to achieve similar results in humans,” said lead study author Chieh-Lun Hsiao, PhD, a post-doctoral fellow in the department of cardiovascular biology and medicine at Juntendo University Graduate School of Medicine in Tokyo.

“If the vaccine could prove to be successful in humans, it would be a big step forward towards delaying disease progression or even prevention of this disease [4].”

In this study, the research team created an Alzheimer’s disease mouse model that mimics a human brain and simulates amyloid-beta-induced Alzheimer’s disease pathology. To test the efficacy of the SAGP vaccine, the mice were treated with a control vaccine or the SAGP vaccine at two and four months old. Usually, people in the late stage of Alzheimer’s lack anxiety, which means they are not aware of the things around them. The mice who received the vaccine had anxiety, which means that they were more cautious and more aware of things around them – a sign researchers say could indicate a lessening of the disease. In addition, several inflammatory biomarkers of Alzheimer’s disease were also reduced.

In Alzheimer’s disease, an accumulation of brain proteins called amyloid beta peptides clump together forming sticky plaques that collect between neurons and disrupt cell function. Vascular problems may also lead to a breakdown of the blood-brain barrier, which usually protects the brain from harmful agents while allowing access for glucose and other necessary factors. This faulty blood-brain barrier prevents glucose from reaching the brain and prevents the clearing away of toxic beta-amyloid and proteins, which results in chronic inflammation and Alzheimer’s disease progression.

The study found that the novel SAGP vaccine significantly reduced amyloid deposits in brain tissue located in the cerebral cortex region, which is responsible for language processing, attention and problem solving. In addition, reduction in inflammatory biomarkers and size of inflammatory molecules was observed, and the SAGP protein was shown to be located very near to specialized brain cells called microglia. Microglia play a role in the immune defense of the central nervous system, helping to clear damaging plaque formed by proteins; however, they also trigger brain inflammation that can damage neurons and worsen cognitive decline in a person, which could be one of the causes of Alzheimer’s disease development.

“Earlier studies using different vaccines to treat Alzheimer’s disease in mouse models have been successful in reducing amyloid plaque deposits and inflammatory factors, however, what makes our study different is that our SAGP vaccine also altered the behavior of these mice for the better,” Hsiao said [4].

According to the researchers, previous research suggests that the SAGP protein is highly elevated in microglia, which means that microglia are very important cells to target in Alzheimer’s disease.

Hsiao said: “By removing microglia that are in the activation state, the inflammation in the brain may also be controlled. A vaccine could target activated microglia and remove these toxic cells, ultimately repairing the deficits in behavior suffered in Alzheimer’s disease [4].”