Blood-brain barrier cells could unlock new Alzheimer’s disease diagnostics and therapy
Targeting the loss of blood-brain barrier cells now implicated in the development of Alzheimer’s disease (AD) may lead to a new diagnostic paradigm and a way forward for drug therapies that improve neurovascular health, according to a study published Dec. 13 in Nature Communications.
A team of researchers including Berislav V. Zlokovic, MD, PhD, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California, Los Angeles, crossbred mice with lower levels of platelet-derived growth factor beta receptor PDGFR-beta, a protein thought to control pericyte growth, with mice bearing the Swedish mutation of human amyloid precursor protein (APP) to see if these factors led to the telltale amyloid plaque, neurofibrillary tangles and neuronal loss typical of AD pathology. Results showed something of a breakthrough in the latter two that other studies have not been able to accomplish, suggesting that vascular disease and in particular the loss of blood vessel cells called pericytes are more important in the development of AD than previously understood.
The loss of pericytes has two major effects: blood-brain barrier deterioration leading to serum protein build-up and potential toxicity from blood products as well as a decrease in microcirculation leading to less brain capillary perfusion and increased tissue hypoxia. This one-two punch results in downstream neuronal changes associated with AD. The study not only demonstrates this process with crossbred mice, but further proves that amyloid build-up alone does not lead to Alzheimer’s disease but instead is a major contributor of disease facilitated by pericyte loss.
“Here we show that pericyte loss in APP mice elevates brain beta amyloid levels and accelerates amyloid angiopathy and cerebral beta-amyloidosis by diminishing clearance of soluble beta amyloid from the brain interstitial fluid prior to beta amyloid deposition,” wrote the authors. “We further show that pericyte deficiency leads to the development of tau pathology and an early neuronal loss that is normally absent in APP mice, resulting in accelerated cognitive decline. Thus, pericyte loss has an effect on multiple steps of AD-like neurodegeneration pathogenic cascade in APP mice suggesting that pericytes may represent a novel therapeutic target to modify disease progression in AD.”
Results showed that the crossbred mice had more pericyte loss compared with both healthy controls and mice with only APP changes or mice with lower PDGFR-beta, revealing the importance of both variables in parallel. Researchers used multiphoton imaging and found that the cortex of pericyte-deficient crossbred mice developed amyloid deposition within 9 months and two-times the human levels of beta amyloid isoforms present in neurodegenerative amyloid plaques.
Further studies are required to investigate whether pericyte rescue could improve neurovascular circulation and alter AD pathology.