A Senolytic Vaccine Targeting SAGP Reduces Pathology in a Mouse Model of Alzheimer's Disease

Researchers have found that senescent cells express a senescence-associated glycoprotein (SAGP) localized to the lysosome, likely an attempted compensatory response to lysosomal stress characteristic of the senescent state. Distinctive features of senescent cells can be used to target them for destruction, thereby reducing the burden they place on aged tissues and achieving some degree of rejuvenation. In today's research materials, researchers report on a demonstration to show that using SAGP as a target to clear senescent cells can reduce pathology in a mouse model of Alzheimer's disease.

These mouse models are highly artificial and embody assumptions about the importance of specific forms of pathology in Alzheimer's disease, as mice do not normally suffer anything resembling this condition, and must thus be altered in ways that produce one or more specific forms of pathology. Nonetheless, the models do share with humans an increased inflammatory activation and senescence of microglia and other supporting cells in the brain. Clearing out the worst of these senescent brain cells via other forms of senolytic treatment has been shown to reduce inflammation and improve symptoms in mouse models of Alzheimer's disease, so it is not too surprising to see the same achieved here.

Novel vaccine may hold key to prevent or reduce the impact of Alzheimer's disease

Previously, researchers developed a vaccine to eliminate senescent cells expressing senescence-associated glycoprotein (SAGP) - a senolytic vaccine that improved various age-related diseases including atherosclerosis and type 2 diabetes in mice. Another study also found that SAGPs are highly expressed in glial cells in people with Alzheimer's disease. Based on the findings from these studies, the researchers tested this vaccine in mice to target SAGP-overexpressed cells to treat Alzheimer's disease.

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 researcher say could indicate a lessening of the disease. In addition, several inflammatory biomarkers of Alzheimer's disease were also reduced.

The 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. The astrocyte cell (the most abundant type of glial cell in the brain and a specific inflammatory molecule) was shown to be decreased in size in mice receiving the vaccine. A reduction in other inflammatory biomarkers was also seen, implying that inflammation in the brain improved in response to the SAGP vaccine. A behavior test on the mice at six months old revealed that those that received the SAGP vaccine responded significantly better to their environment than those who received the placebo vaccine. The SAGP-vaccinated mice tended to behave like normal healthy mice and exhibited more awareness of their surroundings.

The SAGP protein was shown to be located very near to specialized brain cells called microglia, which play a role in the immune defense of the central nervous system. Microglia help 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.