Calcium channel blockers show potential to restore cerebral blood flow in Alzheimer’s disease

Blocking calcium channels in the brain capillaries may improve blood flow and alleviate the damage of early-stage Alzheimer’s, a new study suggests.

Study: Braking Approx²⁺ channels in model mice with Alzheimer’s disease relax pericytes, improve blood flow in the brain, and reduce immune cell blocking and hypoxia. Image credits: Gorodenkoff/Shutterstock.com

From a recent study published in Nature Neuroscienceresearchers used models of Alzheimer’s disease in mice and human brain tissue to investigate whether blocking voltage-gated calcium channels (CaV) could prevent pericytes, cells that line the walls of small blood vessels, from constricting capillaries and restricting blood flow to blood vessels reduce. brain.

Background

Research into therapies for Alzheimer’s disease generally focuses on preventing the formation of amyloid β plaques or hyperphosphorylated tau proteins. However, these therapies have not been successful in preventing the cognitive decline that occurs with the disease, perhaps because significant brain damage has occurred by the time these treatments are administered.

Current research in Alzheimer’s disease has shifted focus to early-stage treatment targets, including cerebral blood flow.

Cerebral blood flow is reduced by 45% in the early stages of Alzheimer’s disease, before the accumulation of amyloid or tau proteins occurs. This reduced blood flow to the brain causes attention and memory disorders and damages the neuronal connections in the brain.

The reduced blood flow is related to capillary constrictions believed to be caused by the pericytes, which contract in response to the reactive oxygen species activated by amyloid β protein.

The constriction of pericytes in only the capillaries and not in the larger blood vessels has been observed in humans and mouse models.

About the study

In the current study, the researchers used nimodipine, a blood-brain barrier-permeable CaV blocker, to reduce capillary contraction induced by pericytes to increase cerebral blood flow, dilate capillaries, and decrease blood viscosity.

The study used several transgenic mouse lines, including those with mutations in Alzheimer’s disease, introducing fluorescent markers for imaging.

The mice were also treated with tamoxifen to inhibit the expression of Cre recombinase mutated estrogen receptor (Cre^ERT2), which allowed specific genes in brain cells to be controlled. Nimodipine treatment was administered via drinking water for a month and a half before the various analytical tests were performed.

In addition, human brain tissue samples were collected from patients undergoing neurosurgery and treated with amyloid β and nimodipine to study the vascular and cellular responses. Pericytes in the capillaries were identified based on morphology and fluorescent labeling.

Advanced microscopic techniques such as two-photon microscopy were used on anesthetized and awake mice in vivo imaging.

In addition, fluorescent dye, laser Doppler flowmetry, and fluorescein isothiocyanate (FITC)-dextran methods were used to measure pericyte activity, cerebral blood flow, and blood-brain barrier integrity.

Changes in blood flow were also monitored using magnetic resonance imaging and laser speckle flowmetry. In addition, the oxygen-poor areas in the brain tissue were labeled by injecting hypoxia markers.

Laser scanning microscopy was used to image reactive oxygen species and the microglia. Two-photon microscopy was also used for calcium ions (Ca²⁺) imaging of brain slices obtained from euthanized mice.

In addition, immunohistochemical methods were performed using various antibodies and fluorescent secondary antibodies for tracing vascular segments and quantifying pericyte coverage.

The antibody targets include the platelet endothelial cell adhesion molecule-1 CD31 and the intercellular adhesion molecule 1 (ICAM-1), which play a role in cellular immune responses.

Results

The researchers found that the contraction of pericytes in capillaries is controlled by CaVs and transmembrane member 16A (TMEM16A), a calcium-activated chloride channel.

These two channels work together to increase Ca²⁺ levels in pericytes, causing the capillaries to constrict. Furthermore, the use of nimodipine decreased Ca²⁺ levels in the pericytes, resulting in vasodilation and increased cerebral blood flow.

Nimodipine was shown to dilate capillaries and arteries in both brain slices and living mice, and the effect was more pronounced in the mouse models of Alzheimer’s disease. The increase in cerebral blood flow was 74% greater in the mouse models of Alzheimer’s disease than that in normal mice, indicating that vascular constriction was also greater in Alzheimer’s disease.

The study also found that the pericytes in even the most distal capillaries played an important role in regulating blood flow, and blocking the calcium channels, even in the more advanced stages of the disease, helped relieve capillary constrictions and improve cerebral blood flow.

The researchers also reported that reactive oxygen species and oxidative stress were important factors in the mechanisms behind reduced cerebral blood flow in Alzheimer’s disease.

The reactive oxygen species generated by amyloid β oligomers and immune cells such as perivascular macrophages and microglia increased Ca²⁺ levels in pericytes, which caused constrictions in the capillaries and disrupted blood flow in the brain.

Using antioxidants such as N-acetylcysteine ​​or inhibiting the enzyme NOX2 (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2), which is involved in the production of reactive oxygen species, was also found to significantly reduce Ca.²⁺ levels in pericytes and increase blood flow.

Conclusions

Overall, the study suggested that targeting the calcium ion channels could help lower Ca²⁺ levels in the pericytes and reduce the reductions in cerebral blood flow seen in Alzheimer’s disease by dilating the capillaries.

The findings also highlighted the role of reactive oxygen species in vascular function in Alzheimer’s disease and indicated that targeting the production of reactive oxygen species could help improve blood flow in the patients.