Alzheimer’s disease (AD) develops through a combination of harmful changes in the brain, including the buildup of amyloid plaques and tau tangles, chronic inflammation, and the gradual loss of neurons. Today’s treatments offer only modest benefits and, in some cases, can disturb homeostasis in the brain or the natural balance of molecules and cell types. Importantly, none of the current treatments provide targeted support to damaged neurons or help restore a healthier brain environment. To address this unmet need, investigators propose a completely different approach: creating engineered cells that act as “on-demand” drug factories. These cells only turn on when Alzheimer’s-related pathology is detected and remain inactive everywhere else.
This idea builds on Dr. Brunger and his team’s innovative use of synthetic biology in Alzheimer’s research. Synthetic biology is an emerging field that treats DNA as programmable code and living cells as customizable factories. The Brunger lab uses synthetic Notch (synNotch), which acts as a sensor on a cell’s surface that can be designed to recognize very specific molecular patterns, such as the aggregated forms of amyloid or tau seen in AD. When these sensors encounter their target, they switch on therapeutic genes chosen by the researchers. The cell’s protein-making machinery then produces the therapeutic proteins. Because synNotch only responds to aggregated forms of these proteins, treatment is delivered precisely at the site of pathology. This targeted approach minimizes unwanted effects elsewhere in the brain.
The Brunger team is applying this technology to human induced pluripotent stem cell (iPSC)–derived astrocytes. Astrocytes normally support neurons and help maintain brain health, but in AD, they can become reactive and contribute to inflammation and degeneration. By equipping astrocytes with synNotch receptors that respond to amyloid or tau, the researchers hope to redirect these cells back toward protective roles. They plan to focus on two key therapeutic factors: BDNF, a molecule that supports neuronal communication and reduces tau activation, and soluble TREM2 (sTREM2), which has shown promise in reducing tau pathology and calming harmful signaling pathways.
In their preliminary work, the team successfully engineered multiple amyloid-responsive synNotch receptors. These receptors activated reliably and selectively in iPSC-derived astrocytes, including when exposed to amyloid from human brains. Astrocytes carrying synNotch-BDNF produced BDNF only in the presence of aggregated amyloid. Similarly, tau-responsive synNotch receptors activated robustly in engineered microglia and iPSC-derived microglia when exposed to purified tau or cell-generated tau in stem cell-based models of tauopathy. In mouse studies, synNotch cells transplanted into an amyloid mouse model (5xFAD) turned on therapeutic genes only in areas with amyloid plaques and not in healthy control animals. These findings demonstrate that the synNotch system can accurately detect AD-related pathology and trigger targeted therapeutic responses in relevant cell types.
The Brunger lab hypothesizes that astrocytes engineered to sense amyloid and tau and respond by producing controlled amounts of BDNF and sTREM2 will reduce neurodegeneration in Alzheimer’s mouse models. They will investigate this hypothesis using three experimental aims. In aim one, they will test whether astrocytes programmed with amyloid-responsive synNotch receptors recognize amyloid plaques in the well-established 5xFAD mouse model and only release helpful factors where plaques are present. The researchers will transplant human stem cell–derived astrocytes into the hippocampus of young 5xFAD and healthy control mice, watch for synNotch activation using a built-in fluorescent signal, and measure whether this targeted response reduces amyloid accumulation or improves markers of neuronal health and communication. For Aim 2, they will evaluate tau-responsive synNotch astrocytes in the PS19 mouse model, which develops abnormal tau tangles like those seen in human AD. Here, they will determine whether engineered astrocytes turn on their therapeutic programs when exposed to harmful tau, and whether this limits tau spread, inflammation, or early signs of nerve-cell damage. As in Aim 1, they will use a mix of imaging, molecular tests, and single-cell analyses to understand how the transplanted cells function in the brain. In Aim 3, they will bring both systems together by introducing astrocytes that can respond to both amyloid and tau. To better mimic the mixed pathology seen in people, the team will seed amyloid-producing 5xFAD mice with human AD-derived tau before transplanting the dual-responsive astrocytes. This final aim will test whether a single engineered cell type can sense multiple disease signals at once and coordinate a broader, more effective protective response. Together, these experiments will show whether engineered astrocytes can survive long-term in the brain, deliver therapeutic factors only when needed, and ultimately influence memory-related outcomes.
If successful, this work would demonstrate a new kind of treatment — living, engineered cells that can sense harmful changes in the brain and deliver therapy precisely where it is needed. This approach has the potential to address multiple aspects of AD at once and could pave the way for a new generation of highly targeted, adaptive treatments.
