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New Model Allows Screening of Drugs to Improve Blood–Brain Barrier Integrity in Alzheimer's Disease

Key findings

  • Cell culture models exist for studying blood–brain barrier (BBB) dysfunction associated with Alzheimer's disease (AD), but they lack many features of the human brain in AD
  • Researchers at Massachusetts General Hospital have created a three-dimensional human neural cell culture microfluidic model that has a brain endothelial cell (bEC) layer, which has a BBB-like phenotype
  • The AD model exhibits key events in AD pathogenesis and reflects several vascular alterations that are observed in patients with AD
  • Etodolac significantly decreased the permeability of the bEC barrier and was protective against the neurotoxic effects of thrombin
  • The study suggests that drugs that increase BBB integrity may have therapeutic potential against AD and that the new model can be used for drug screening

Dysfunction of the blood–brain barrier (BBB) is now considered a key factor in the cause and consequences of Alzheimer's disease (AD). Substantial evidence suggests that in patients with AD or mild cognitive impairment, the BBB doesn't properly regulate the transport and clearance of brain β-amyloid (Aβ) or other harmful materials.

BBB impairment associated with AD has been studied by culturing brain endothelial cells (bECs), a major component of the BBB, and treating them with synthesized Aβ peptides. However, these models lack many features of the human brain in AD.

Rudolph E. Tanzi, PhD, co-director of the McCance Center for Brain Health and vice-chair of the Department of Neurology, and Se Hoon Choi, PhD, assistant professor of neurology at Massachusetts General Hospital, and colleagues previously developed a cell culture system on a three-dimensional microfluidic chip that exhibits key events in AD pathogenesis, including extracellular aggregation of Aβ and accumulation of hyperphosphorylated tau. However, that model lacks a BBB. That research was published in Nature.

In a new study published in Advanced Science, Dr. Tanzi and Dr. Choi, in collaboration with Roger D. Kamm, PhD, at the Massachusetts Institute of Technology, and colleagues report that they have re-engineered the AD culture system to include a bEC barrier that mimics the cerebral–vascular interface to facilitate the study of how the AD pathological microenvironment affects bECs.

Recapitulating the Vascular Alterations of AD

The earlier model makes use of ReNcell VM human neural progenitor cells that express familial AD mutations in the APP and APP/PSEN1 genes. In the current study, a model containing these ReN-AD cells was compared with one containing wild-type ReN cells.

The AD model reflected several vascular alterations that are observed in patients with AD. In the AD model compared with the wild-type model:

  • The permeability of the bEC barrier was significantly increased
  • Expression of two tight junction proteins (claudin-1 and claudin-5) and an adherens junction protein (vascular endothelial cadherin) was reduced in bECs
  • Levels of reactive oxygen species, matrix metalloproteinase-2 and interferon-gamma were increased in bECs. All of these have been shown to impair BBB function in AD
  • Aβ was deposited around cerebrovascular blood vessels only in the AD model

Reducing Aβ Decreases BBB Permeability

The investigators next treated ReN-AD cells with an investigational drug that blocks the β-secretase enzyme and therefore prevents the production of Aβ. The treatment significantly decreased BBB permeability, suggesting that Aβ itself or Aβ-driven changes in other molecules contribute to BBB impairment.

Effects of BBB Permeability on Neuronal Damage

The results of a separate experiment supported the hypothesis that circulating neurotoxins can enter the brain through the disrupted BBB and exacerbate the progression of AD. The researchers introduced thrombin, a bloodborne enzyme that is directly neurotoxic, into the AD model. Thrombin was able to pass the leaky BBB, and it exacerbated the loss of neurons.

In a previous study, the drugs etodolac and beclomethasone were able to protect the integrity of the BBB against Aβ toxicity in a mouse model of AD. The researchers used each of those drugs to treat the impaired bEC barrier in the AD model. Etodolac, but not beclomethasone, significantly decreased the permeability of the bEC barrier compared with the vehicle.

Finally, the researchers treated the AD model with etodolac or the vehicle, then introduced thrombin into the bEC barrier. The level of dead ReN-AD cells was significantly lower with etodolac than with the vehicle.

Interpreting the Findings

The effects of etodolac and beclomethasone might be different because bEC dysfunction in the new AD model is affected not only by Aβ peptides but also by other pathological environmental stimuli such as cytokines from AD cells. If so, the study findings suggest that the new model more realistically replicates in vivo behavior than the older ones do.

Even more exciting, the study suggests that drugs that increase BBB integrity may have therapeutic potential against AD. The new AD model provides a standardized platform for moderate-throughput screening of drugs that might inhibit BBB dysfunction or enhance BBB integrity as an adjunct to other AD therapies.

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