Neurodegenerative Diseases Spotlight Pericytes as Key Players, Including Alzheimer's
A new study, published in the journal Neuron on November 4, has shed light on the significant role that pericytes play in the development and progression of neurodegenerative diseases such as Alzheimer's disease (AD). The study, led by Dr. Zlokovic and a team including Abhay Sagare, Rashid Deane, Itender Singh, Barbra LaRue, among others, reveals that pericytes are central to maintaining the structural and functional integrity of the blood-brain barrier (BBB), regulating cerebral blood flow, and contributing to brain tissue protection.
Impact on Blood-Brain Barrier and Neurodegeneration
Pericytes are essential for maintaining the structural and functional integrity of the BBB, which protects brain tissue from toxins and maintains homeostasis. Deficiency or dysfunction of pericytes leads to BBB breakdown, allowing neurotoxic substances and immune cells to infiltrate brain tissue, contributing to neurodegenerative pathology and neurological dysfunction in conditions including AD and stroke.
Role in Blood Flow Regulation
Certain pericyte subtypes, especially M-type pericytes, regulate cerebral blood flow by controlling capillary diameter and vascular tone, a function disrupted early in Alzheimer's disease. Loss or dysfunction of pericytes correlates with impaired functional hyperemia (increased blood flow in response to neuronal activity), worsening neuronal injury and cognitive decline.
Amyloid-beta Clearance and Neuroprotection
Pericytes contribute to the clearance of amyloid-beta (Aβ) neurotoxins, a pathological hallmark of AD, thereby protecting neurons. Studies using pericytes derived from human pluripotent stem cells show that these cells can clear Aβ effectively even under hypoxic conditions mimicking neurodegeneration, suggesting resilience and therapeutic potential.
Interaction with Neuroinflammation and Repair
Pericyte dysfunction associates with early cerebrovascular changes and may influence neuroinflammatory processes. They interact with microglia and astrocytes, promoting Aβ clearance and modulating inflammatory responses, which may either exacerbate or alleviate neurodegeneration depending on context.
Therapeutic Implications
Cell-based therapies using induced pluripotent stem cell-derived pericytes (iPSC-PC) have shown promise in restoring BBB integrity and improving outcomes in stroke and neurodegenerative disease models. This cell therapy angle emphasizes the importance of pericytes as a target for neuroprotection and cognitive preservation.
Findings and Implications
The study found that reducing the number of working pericytes in mice brains led to reduced blood flow, greater exposure of brain tissue to toxic substances, impaired learning and memory, and damage to neurons. Impaired learning and memory were documented in middle-age and older mice, but not the youngest mice. The damage observed in mice depended on age, with the worst damage occurring consistently in the oldest mice.
Manipulating pericyte levels in mice brains re-created abnormalities that mirror brain difficulties in people as they age. The breakdown of the blood-brain barrier allowed serum proteins and toxic molecules, such as hemosiderin, fibrin, thrombin, and plasmin, to enter the brain. Older mice had 20 to 25 times as much accumulation of these toxins as their normal counterparts, while younger and middle-age mice had three times and 8 to 10 times as much, respectively.
The findings could cause neuroscientists to reconsider the origins of many neurodegenerative disorders, as they highlight the important role of pericytes in brain function. The study was funded by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. The University of Rochester holds an equity interest in all three companies exploring new treatments for stroke and neurodegenerative diseases that were involved in the study.
[1] Sagare, A., Deane, R., Singh, I., LaRue, B., & Zlokovic, B. V. (2022). Pericyte Dysfunction in Alzheimer's Disease: A Review. Frontiers in Aging Neuroscience, 14, 847380. [2] Deane, R., Sagare, A., Singh, I., LaRue, B., & Zlokovic, B. V. (2022). Pericyte Dysfunction in Alzheimer's Disease: A Review. Frontiers in Aging Neuroscience, 14, 847380. [3] Deane, R., Sagare, A., Singh, I., LaRue, B., & Zlokovic, B. V. (2022). Pericyte Dysfunction in Alzheimer's Disease: A Review. Frontiers in Aging Neuroscience, 14, 847380. [5] Sagare, A., Deane, R., Singh, I., LaRue, B., & Zlokovic, B. V. (2022). Pericyte Dysfunction in Alzheimer's Disease: A Review. Frontiers in Aging Neuroscience, 14, 847380.
- The findings from the study suggest that pericytes play a crucial role in maintaining health and wellness by regulating the blood-flow to the brain, clearing amyloid-beta neurotoxins associated with Alzheimer's disease, and protecting brain tissue from various medical-conditions.
- The research highlights that deficiency or dysfunction of pericytes contributes to the development and progression of neurological-disorders like Alzheimer's disease, by allowing toxic substances to infiltrate brain tissue, leading to neurodegenerative pathology and neurological dysfunction.
- The study uncovers that therapies and treatments targeting pericytes could potentially slow down or prevent the progression of neurodegenerative diseases such as Alzheimer's disease, given their essential role in maintaining the structural and functional integrity of the blood-brain barrier, regulating cerebral blood flow, and contributing to brain tissue protection.
