Abstract
Harmful materials in the blood are prevented from entering the healthy brain by a highly selective blood–brain barrier (BBB), and impairment of barrier function has been associated with a variety of neurological diseases. In Alzheimer's disease (AD), BBB breakdown has been shown to occur even before cognitive decline and brain pathology. To investigate the role of the cerebral vasculature in AD, a physiologically relevant 3D human neural cell culture microfluidic model is developed having a brain endothelial cell monolayer with a BBB‐like phenotype. This model is shown to recapitulate several key aspects of BBB dysfunction observed in AD patients: increased BBB permeability, decreased expression of claudin‐1, claudin‐5, and VE‐cadherin, increased expression of matrix‐metalloproteinase‐2 and reactive oxygen species, and deposition of β‐amyloid (Aβ) peptides at the vascular endothelium. Thus, it provides a well‐controlled platform for investigating BBB function as well as for screening of new drugs that need to pass the BBB to gain access to neural tissues.
Highlights
AD-associated blood–brain barrier (BBB) impairment have previously been developed using cultures of brain endothelial cells (bECs) on transwell inserts, incubatedAlzheimer’s disease (AD) is the most common form of age- with high concentration of synthesized Aβ peptides for short related dementia, characterized pathologically by deposition periods
We previously developed a 3D human neural cell culture model of AD in which human-origin neural progenitor cells (NPCs) expressing amyloid precursor protein (APP) or APP/presenilin 1 (PSEN1) with familial AD (FAD) mutations grow to maturity in a 3D culture system.[10,11]
We previously reported a unique strategy for recapitulating AD pathology, namely Aβ-driven neurofibrillary tangles, in a human NPC-derived 3D Matrigel culture system.[10,11]
Summary
AD-associated BBB impairment have previously been developed using cultures of bECs on transwell inserts, incubated. We previously developed a 3D human neural cell culture model of AD in which human-origin neural progenitor cells (NPCs) expressing amyloid precursor protein (APP) or APP/presenilin 1 (PSEN1) with familial AD (FAD) mutations grow to maturity in a 3D culture system (referred as “3D AD” culture).[10,11] Our 3D AD culture exhibits key events in AD pathogenesis, including extracellular aggregation of Aβ and accumulation of hyperphosphorylated tau This model lacks a BBB, and is limited in its ability to study the role of BBB biology and function in AD. We demonstrate that our AD model serves as a wellcontrolled platform to understand physiological and pathological mechanisms of BBB dysfunction in AD and can usefully be employed as a standardized therapeutic drug screening platform
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