Modeling neurovascular dysfunction in Alzheimer's disease using an isogenic brain-chip model

Area of Science:

• Neuroscience
• Biotechnology

Background:

• Alzheimer's Disease (AD) pathology involves amyloid beta (Aβ) plaques and tau tangles.
• Neurovascular dysfunction, including increased blood-brain barrier (BBB) permeability and reduced Aβ clearance, are early AD markers.
• Current treatments for AD dementia are limited, necessitating novel therapeutic approaches and advanced in-vitro models.

Purpose of the Study:

• To develop and utilize a novel New Alternative Method (NAM) brain-chip model.
• To investigate neurovascular unit (NVU) dysfunction in Alzheimer's Disease using patient-derived cells.
• To evaluate AD-like pathology and its impact on NVU function in a human induced pluripotent stem cell (hiPSC)-based model.

Main Methods:

• A brain-chip model of the cortical neurovascular unit (NVU) was created using hiPSCs from an AD patient and a healthy individual.
• Neurons, astrocytes, pericytes, microglia, and brain microvascular endothelial cells were differentiated and cultured in a microphysiological system.
• The model was used to assess NVU-related endpoints, including barrier integrity, transporter activity, protein levels, and inflammatory markers.

Main Results:

• AD brain-chips exhibited reduced claudin-5 and ZO-1 expression, increased paracellular permeability, and decreased P-glycoprotein (P-gp) activity.
• Aβ42 levels were decreased in the brain channel, while tau and phosphorylated tau (p-tau 181) increased in the vascular channel of AD brain-chips.
• Proinflammatory markers IL-6 and MCP-1 were elevated in both brain and vascular channels of the AD brain-chips.

Conclusions:

• The brain-chip model demonstrated Aβ-independent NVU dysfunction linked to neuroinflammation and vascular tau accumulation.
• This study validates the brain-chip model for evaluating AD-related NVU changes and highlights donor-specific responses in hiPSC models.
• The findings suggest potential therapeutic targets related to neuroinflammation and vascular tau in Alzheimer's Disease.