Dementia currently affects more than 57 million people worldwide and is projected to affect some 150 million by 2050. And up to 80% of people diagnosed with dementia have Alzheimer’s disease.
People with Alzheimer’s disease experience a range of symptoms, which usually start with memory issues, confusion, coordination problems, personality changes, and difficulty completing familiar tasks.
Changes in the brain that lead to these symptoms include the buildup of amyloid beta (Aβ) and tau proteins, as well as inflammation. Studies suggest that these may, in part, result from changes in the blood-brain barrier (BBB) — a semipermeable membrane in the small blood vessels that shields the brain from toxic substances and supplies the brain with nutrients.
Now, a study led by researchers at the Mayo Clinic in Florida has found unique molecular changes in the blood-brain barrier of people with Alzheimer’s disease, markers of which can be detected in the blood.
The study, which is published in Nature Communications, suggests that these molecular signatures could lead to new methods for diagnosing and treating Alzheimer’s disease.The blood-brain barrier lines capillaries (the smallest blood vessels) in the brain and is made up of three cell types — endothelial cells, pericytes, and astrocytes — plus capillary basement membrane.
In healthy people, these structures work together to control the passage of molecules between the blood and the nervous system, ensuring that harmful molecules do not reach the brain. However, in Alzheimer’s disease, this system can break down.
In this study, the researchers used postmortem brains donated by 12 people with Alzheimer’s disease and 12 without to investigate the changes in the blood-brain barrier. Using these samples and external data sets, they analyzed thousands of cells from many regions of the brains.
They examined molecular changes associated with Alzheimer’s disease, primarily in the vascular tissue, focusing on pericytes that maintain the integrity of the blood-brain barrier, and astrocytes, the support cells.The discovery of unique molecular signatures related to blood-brain barrier dysfunction in Alzheimer’s disease (AD) could revolutionize diagnosis and treatment.To further investigate the effect of SMAD3, the researchers took blood samples from living older volunteers. Those whose blood contained higher levels of SMAD3 showed lower levels of Alzheimer’s pathology, such as amyloid deposits and brain shrinkage.
The authors caution that their findings cannot determine whether elevated SMAD3 levels and signaling damage the blood-brain barrier, or are a protective response to Alzheimer’s pathologies.
Blood SMAD3 level associations per se do not prove causality, they indicate a potential role of this molecule for Alzheimer’s in both brain and periphery. Taken together, our findings support a model wherein VEGFA reduction and signaling in the presence of Aβ (and possibly other Alzheimer’s neuropathologies) lead to increased SMAD3 levels, signaling, and BBB disintegrity.
