Bringing light to dark places: Illuminating the cellular causes of Alzheimer’s disease
June is Alzheimer’s & Brain Awareness month. Every year, to honor those who suffer from this disease and their families, we highlight Alzheimer’s disease researchers that are working to shed light on the mechanisms—and potential treatments—that will help end this debilitating disease.
It started small: a lapse in memory where they didn’t remember to turn off the stove, or what they had for lunch. It progressed to forgetting familiar tasks. Then words began to disappear. Then names. Then faces.
Statistically speaking, you are familiar with this scenario, either firsthand or from a friend or family member who is. It is a unique brand of pain, made worse by the constant refrain of, “There is nothing I can do for them.” This is the reality for the more than 30 million people (1) that suffer from Alzheimer’s disease and their loved ones: watching this disease, this intangible monster, take and take until there is nothing left.
But science teaches us that it is not intangible, it is physical. It has form—a root cause—and that lets us fight back: because Alzheimer’s disease may be complex, and it may be devastating, but it is not unsolvable. So, in recognition of Alzheimer’s & Brain Awareness Month, we’re highlighting one of the many research groups who are bringing light into the dark corners of this disease.
Illuminating vascular risk factors for Alzheimer’s disease
The brain uses more energy than any other organ, and delivering that energy requires extensive vasculature. While dysfunction of the neurovasculature compromises brain function, and can even cause dementia, we still know frustratingly little about how this system contributes to Alzheimer’s disease (AD).
This lack of knowledge spurred Dr. Wyss-Coray’s laboratory (Stanford University) to investigate how individual cell types within the neurovasculature can mediate AD risk (2). Using a newly developed in-house vessel isolation protocol combined with Chromium Single Nuclei Gene Expression, researchers performed single nuclei RNA sequencing (snRNA-seq) on the vasculature of nine patients with AD and eight controls. This novel approach enabled them to collect and characterize more than 200 times the amount of vascular nuclei (143,793) than had been reported in prior experiments.
These findings revealed significant reductions in endothelial, smooth muscle, and fibroblast-like cells in AD consistent with widespread vascular loss. 463 differentially expressed genes were identified across a variety of cell types, with multiple genes having been identified as AD risk loci in GWAS studies. Combined, this vascular AD signature was consistent with disrupted blood flow and offers a potential mechanism behind the reduced cerebral perfusion seen in AD patients.
Nearly 60% of total AD risk genes are expressed in (peri)vascular cells, and multiple risk genes were enriched in vascular cells. Surprisingly, however, a multitude of immune-related AD risk genes were also enriched in arterial cells, capillaries, smooth muscle cells, and pericytes. Many immune-related genes—including the risk factor APOE—were expressed in both vasculature and microglia in humans, but restricted to microglia in mice. As mice do not normally develop AD (and require genetic intervention to recapitulate AD-like phenotypes), this led the group to hypothesize a microglia–vascular axis as a potential mechanism that underlies (or enhances) AD risk.
Shining a light on the path ahead
It has been 116 years since Alois Alzheimer first described Alzheimer’s disease—but it has been only 37 years since the discovery of PCR, 22 years since next-generation sequencing, and less than 10 since single cell sequencing. For those of us with loved ones suffering from Alzheimer’s disease, the progress towards a treatment feels agonizingly slow. However, the pace of progress is accelerating, buoyed by the insights of research groups like that of Dr. Wyss-Coray.
Alzheimer’s disease is heterogeneous and complex, but it is far from impossible to understand. And, armed with research tools and technologies that would have been unimaginable even thirty years ago, we are moving towards a brighter future, faster than ever before.
Finally, in recognition of Alzheimer’s & Brain Awareness Month, we want to thank Dr. Wyss-Coray’s group, as well as the larger Alzheimer’s disease and related dementias research community. Your research lights the path towards a better understanding—and eventual treatment—of Alzheimer’s disease and shows that, by working together, we are capable of moving mountains.
Read the publication for yourself and go deeper into what they found, or discover how new approaches using single cell, spatial, and in situ tools are helping researchers like you illuminate the underlying architecture of disease.
References:
-
Dementia. Who.int. https://www.who.int/news-room/fact-sheets/detail/dementia
-
Yang AC, et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603: 885–892 (2022). doi: 10.1038/s41586-021-04369-3