Researchers have discovered specific brain regions in mice that are particularly susceptible to blood vessel deterioration, shedding light on the link between vascular health and neurodegenerative diseases.
Maintaining healthy blood vessels is essential not just for heart health but also for brain health, and may play a role in mitigating age-related cognitive decline and neurodegenerative diseases such as Alzheimer’s disease, based on a recent study conducted by researchers at Penn State. This research highlights the importance of the brain’s vascular system—which can be thought of as its energy infrastructure—in the development of neurodegenerative conditions.
Their findings were published today (July 30) in Nature Communications.
Utilizing advanced imaging methods, the research team created maps of mouse brains to showcase how blood vessels and vascular cells transform with age while identifying regions prone to decline. As blood vessels deteriorate, neurons lose energy, leading to their dysfunction or death. This process can result in vascular dementia, which is the second most common cause of cognitive decline in the elderly, manifesting as issues like sleep disturbances.
“In the case of Alzheimer’s disease, significant changes in the vascular system and noticeable brain shrinkage on an MRI often occur after cell death has already taken place. It’s imperative that we comprehend the alterations in cells and vascular structures before a major disaster strikes,” stated Yongsoo Kim, an associate professor at Penn State College of Medicine and the senior author of the study. “This research offers early indicators of neurodegenerative diseases, potentially allowing for earlier detection and insights into how we might slow down aging and cognitive decline.”
According to Kim, aging is a primary factor contributing to neurodegenerative diseases.
“However, we lack a solid foundational understanding of how typical aging affects the brain, especially its vascular system,” Kim noted. As the aging population in the United States continues to grow, he emphasized the need to study these changes within the blood vessel network.
Blood vessels, particularly the smaller micro-vessels, are crucial for supplying oxygen and energy to neurons and removing waste. Despite their significance, much of the existing research focuses mainly on the degeneration of neurons instead of the vascular components. When investigations do address the brain’s vascular system, they often concentrate on larger blood vessels or rely on a specific, easily accessible area of the brain, like the somatosensory cortex. Moreover, typical neuroimaging techniques, such as MRI, often lack the resolution needed to visualize the tiny blood vessels that represent 80% to 85% of the brain’s vascular system, according to Kim.
Kim and the research team successfully constructed a comprehensive map of the mouse brain’s vascular system using two high-resolution 3D mapping techniques: serial two-photon tomography, which produces a sequence of layered 2D images, and light sheet fluorescence microscopy, which captures entire intact 3D samples at the resolution of individual cells. They analyzed the brains of both young and old mice to observe how the vascular structure evolves with normal aging.
“By utilizing high-resolution mapping, we can reconstruct the entire vascular framework and examine the whole brain to identify specific regions experiencing degeneration as they age,” Kim remarked. “Interestingly, we found that the most commonly studied areas showed the least amount of change, while significant transformations occurred in deeper sections of the brain. This indicates that our focus may have been misplaced in aging studies.”
The imaging revealed that changes in the vascular network are not uniform across the brain. Instead, they are concentrated in regions such as the basal forebrain, the deeper cortical layers, and the hippocampal network—areas recognized for their roles in attention, sleep regulation, memory processing, and storage.
As brains age, the length and branching density of blood vessels decline by about 10%, signifying a less dense network for blood distribution. Additionally, arteries in older brains tend to twist more than those in younger brains, potentially hindering blood flow, particularly to regions distant from the primary arteries, such as deeper cortical layers, according to Kim.
The study also explored functional shifts within the vascular system, revealing that it operates more slowly in older brains. Consequently, it struggles to provide neurons with energy as promptly as is often required. There is also a noted decrease in pericytes, which are cells critical for managing blood supply and vessel permeability. This leads to increased “leakiness” of blood vessels, thus compromising the integrity of the blood-brain barrier.
This research builds upon earlier investigations conducted by the team, in which they mapped the vascular system of young mouse brains. They now plan to explore how changes induced by Alzheimer’s disease affect vascular health and neuronal function. Their ultimate goal is to pave the way for potential treatments for neurodegenerative diseases.
Co-leading the study were Hannah Bennett, a dual medical degree and PhD student, and Steffy Manjila, a postdoctoral scholar, along with Quingguang Zhang, who was previously an assistant research professor at Penn State and is now an assistant professor at Michigan State University, and Yuan-ting Wu, a former research scientist at Penn State who is currently a project scientist at Cedars-Sinai Medical Center. Other contributors from Penn State include Patrick Drew, a professor across multiple fields including engineering science and biomedical engineering; Uree Chon, a research technician; Donghui Shin, a research technologist; Daniel Vanselow, a research project manager; and Hyun-Jae Pi, a data scientist.
This research was supported by funding from the National Institutes of Health and the American Heart Association.
