The new study, which is the first to demonstrate that CA-VB inhibition can reduce Alzheimer’s disease-mediated cerebrovascular dysfunction and cognitive impairment, was published in the journal Science Advances.
By the time declines in memory and cognition surface in Alzheimer’s disease, blood vessels in the brain have already suffered extensive damage. The same is true for mitochondria – the energy-generating powerhouses of cells. These events are also the basis of cerebral amyloid angiopathy (CAA), a vascular condition that frequently occurs alongside Alzheimer’s disease, accelerating decays in neuron function that underline memory loss.
Alzheimer’s prevention depends heavily on stopping processes that contribute to cerebrovascular dysfunction and neuroinflammation, and now, researchers at The Lewis Katz School of Medicine at Temple University show that blocking a mitochondrial enzyme known as carbonic anhydrase VB (CA-VB) may hold the answer. In experiments in human cells and an Alzheimer’s disease mouse model, they found that selectively blocking CA-V with a drug or by genetic depletion protected blood-vessel function and reduced signs of brain inflammation while preserving memory.
The new study, which is the first to demonstrate that CA-VB inhibition can reduce Alzheimer’s disease-mediated cerebrovascular dysfunction and cognitive impairment, was published online October 14 in the journal Science Advances.
“CA inhibition is linked to reduced vascular inflammation and improved cognition, though the relationship is complex,” explained senior investigator Silvia Fossati, PhD, Scott Richards North Star Foundation and Stop Alzheimer’s Now Chair in Alzheimer’s Research, Professor of Neural Sciences, and Director of the Alzheimer’s Center at the Lewis Katz School of Medicine at Temple.
In previous work, Dr. Fossati and colleagues found that accumulation of a protein known as amyloid-beta, one of the main pathological features of Alzheimer’s disease, renders mitochondria largely dysfunctional and that this process is linked to CA activity. “We also know from experiments in cells that CA inhibitors can mitigate the impacts of impaired mitochondrial function and reduce cell death linked to amyloid,” Dr. Fossati said.
Dr. Fossati’s team also previously demonstrated that pan-CA inhibitors protect against CAA pathology and cognitive decline and identified mitochondrial CA-VB as the specific isoform upregulated in Alzheimer’s disease and CAA. It remained unknown, however, whether selectively inhibiting mitochondrial CA-V, and particularly CA-VB, can both protect against amyloid-induced damage and reduce the impact of undesired off-target effects of pan-CA inhibition.
To gain a more complete picture, Dr. Fossati’s team, led by PhD candidate and now postdoctoral fellow Nicole L. Lemon, carried out investigations in cerebral vascular cells and in mice that develop Alzheimer’s disease. In the animal model, affected mice exhibit increasing amounts of human amyloid and tau proteins as they age, accompanied by signs of cerebrovascular dysfunction and eventually cognitive impairment.
In the course of the team’s experiments, the animals were treated with a CA-V selective inhibitor from the time Alzheimer’s pathology first emerged until advanced cognitive impairment was present. When the researchers examined brain tissue from treated mice, they found significant improvements in the health of the cerebral vasculature. They also found that glial cells, which support neurons, were overall healthier and that neuroinflammation was reduced. In addition, treated animals had significantly preserved cognitive ability and memory compared to untreated animals.
The cell studies further showed that selectively inhibiting or genetically depleting mitochondrial CA-VB improved vascular cell responses to amyloid, in addition to preventing endothelial cell death and mitochondrial dysfunction.
“The C-V inhibitor was highly effective in improving cerebrovascular and neurovascular function,” Dr. Fossati said. “Our behavioral studies showed that, as Alzheimer’s vascular and inflammatory pathology decreased, mice treated with the CA-V inhibitor also experienced noticeable gains in cognitive function and memory.”
The group plans next to design and investigate new CA inhibitors that are even more specific to mitochondrial CA-VB, with the help of Marc Ilies, PhD, Professor in the Moulder Center for Drug Discovery Research at the Temple School of Pharmacy. “If we can target the enzyme more specifically within brain mitochondria, the efficacy of therapy could improve greatly, and side effects could be reduced,” Dr. Fossati explained.
Clinical trials to test the effectiveness of the pan-CA inhibitors acetazolamide and methazolamide against Alzheimer’s disease and CAA in humans could be underway soon, as both agents are already approved by the U.S. Food and Drug Administration.
Other researchers who contributed to the new study include Elisa Canepa, Rafael Vazquez-Torres, Rebecca Parodi-Rullan, Tina Hirt, and Maryam H. Abyaneh, Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine; and Lisa M. Petersohn, Tashnuva Rifat, and Marc A. Ilies, Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy.
Funding was provided in part by grants from the National Institutes of Health, The Alzheimer’s Association, the Karen Toffler Charitable Trust, the Thome Foundation, and the Pennsylvania Department of Health Collaborative Research on Alzheimer’s Disease.