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Capillary Stalling: A Mechanism of Decreased Cerebral Blood Flow in AD/ADRD
Reece Crumpler1, Richard J Roman1, Fan Fan1
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Insights
Targeting stalled capillaries, a new mechanism in Alzheimer's Disease (AD) and related dementias (ADRD), may improve cerebral blood flow (CBF) and cognitive function in affected individuals.
Area of Science:
- Neuroscience
- Vascular Biology
- Pathology
Background:
- Alzheimer's Disease (AD) and related dementias (ADRD) are linked to aging and comorbidities like diabetes and hypertension.
- Vascular dysfunction, including reduced cerebral blood flow (CBF), is a key feature of AD/ADRD progression.
- Capillary stalling, or temporary arrest of capillary blood flow, contributes to cerebral hypoperfusion and cognitive decline in AD/ADRD.
Purpose of the Study:
- To investigate capillary stalling as a mechanism contributing to cerebral hypoperfusion in Alzheimer's Disease.
- To explore potential therapeutic targets for reducing capillary stalling and improving CBF in AD.
Main Methods:
- Studies were conducted using Alzheimer's Disease mouse models.
- Researchers examined the role of inflammation in capillary stalling.
- Investigated the effects of inhibiting specific targets, Ly6G and VEGF-A, on capillary stalling and CBF.
Main Results:
- Chronic inflammation in AD/ADRD contributes to capillary stalling via increased cell adhesion molecules and leukocyte activity.
- Separate inhibition of Ly6G and VEGF-A reduced capillary stalling in AD mice.
- These interventions also led to increased cerebral blood flow (CBF) in the studied models.
Conclusions:
- Capillary stalling is a significant factor in cerebral hypoperfusion and cognitive impairment in Alzheimer's Disease.
- Targeting stalled capillaries, potentially through Ly6G or VEGF-A inhibition, shows promise for future AD/ADRD therapies.
- Modulating capillary stalling could offer a novel therapeutic strategy for improving outcomes in Alzheimer's Disease and related dementias.
Abstract:
Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are debilitating conditions that are highly associated with aging populations, especially those with comorbidities such as diabetes and hypertension. In addition to the classical pathological findings of AD, such as beta-amyloid (Aβ) accumulation and tau hyperphosphorylation, vascular dysfunction is also associated with the progression of the disease. Vascular dysfunction in AD is associated with decreased cerebral blood flow (CBF). Impaired CBF is an early and persistent symptom of AD/ADRD and is thought to be associated with deficient autoregulation and neurovascular coupling. Another recently elucidated mechanism that contributes to cerebral hypoperfusion is capillary stalling, or the temporary arrest of capillary blood flow usually precipitated by a stalled leukocyte or constriction of actin-containing capillary pericytes. Stalled capillaries are associated with decreased CBF and impaired cognitive performance. AD/ADRD are associated with chronic, low-level inflammation, which contributes to capillary stalling by increased cell adhesion molecules, circulating leukocytes, and reactive oxygen species production. Recent research has shed light on potential targets to decrease capillary stalling in AD mice. Separate inhibition of Ly6G and VEGF-A has been shown to decrease capillary stalling and increase CBF in AD mice. These results suggest that targeting stalled capillaries could influence the outcome of AD and potentially be a target for future therapies.
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