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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized in part by the accumulation of the protein amyloid-{beta} (A{beta}). Monoclonal antibodies (mAbs) that target A{beta} for clearance from the brain have received FDA approval; however, these therapies are accompanied by serious side effects, and their cognitive benefit for patients remains of tremendous debate. Here, we present a potential engineered cell therapy for AD in which we enlist cells of the central nervous system as programmable agents for sculpting the neurodegenerative niche toward one that mitigates glial reactivity and neuronal loss. We constructed a suite of A{beta}-sensitive synthetic Notch (synNotch) receptors from clinically tested anti-A{beta} mAbs and show that cells expressing these receptors can recognize synthetic A{beta}42 and A{beta}40 with differential sensitivity. We express these receptors in astrocytes, cells native to the brain that are known to become dysfunctional in AD. These synNotch astrocytes, which upregulate selected transgenes upon exposure to synthetic and human brain-derived amyloid, were engineered to express potential therapeutic transgenes in response to A{beta}, including brain-derived neurotrophic factor and antagonists of the cytokines tumor necrosis factor and interleukin-1. SynNotch astrocytes that express such antagonists in response to A{beta} partially attenuate a cytokine-induced reactive astrocyte phenotype and promote barrier properties in brain microvascular endothelial cells. Additionally, engineered A{beta}-synNotch cells potently upregulate transgene expression in response to A{beta} deposited in the 5xFAD mouse brain, demonstrating the capacity to recognize A{beta} in situ. Overall, our work supports A{beta}-synNotch receptors as promising tools to generate a cell-based therapy for AD with targeted functionalities to positively influence the AD niche.