Amyloid-β-regulated gene circuits for programmable Alzheimer's disease therapy

Area of Science:

• Neuroscience
• Biotechnology
• Cell Therapy

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) accumulation, with current antibody therapies showing debated efficacy and side effects.
• Central nervous system cells, particularly astrocytes, become dysfunctional in AD and contribute to neurodegeneration.

Purpose of the Study:

• To develop an engineered cell therapy for AD using synthetic Notch (synNotch) receptors to program astrocytes.
• To create Aβ-sensitive synNotch receptors capable of recognizing and responding to amyloid-beta in the brain.

Main Methods:

• Constructed synNotch receptors using clinically tested anti-Aβ monoclonal antibodies (mAbs).
• Expressed synNotch receptors in astrocytes, enabling them to upregulate therapeutic transgenes upon Aβ detection.
• Tested engineered astrocytes in vitro and in the 5xFAD mouse model of AD.

Main Results:

• Engineered astrocytes recognized synthetic Aβ42 and Aβ40 with differential sensitivity.
• SynNotch astrocytes upregulated transgenes like brain-derived neurotrophic factor and cytokine antagonists in response to Aβ.
• Engineered cells partially attenuated reactive astrocyte phenotypes and promoted endothelial barrier properties.
• Demonstrated potent Aβ-induced transgene expression in engineered cells within the 5xFAD mouse brain.

Conclusions:

• Aβ-synNotch receptors are promising tools for developing targeted, cell-based AD therapies.
• This approach offers a strategy to reprogram the neurodegenerative niche, mitigating glial reactivity and neuronal loss.
• Engineered cell therapy holds potential for positively influencing the AD pathological environment.