CARs trained on Alzheimer’s antibodies can detect toxic tau and amyloid, raising the possibility of targeted, mobile brain cell therapies.
Immunotherapy, long the domain of oncology, may soon have a new frontier in neurodegeneration. A team at the Buck Institute for Research on Aging has repurposed the technology behind chimeric antigen receptors (CARs) – best known for their role in cancer treatment – to recognize and respond to two key hallmarks of Alzheimer’s disease: tau tangles and toxic amyloid plaques. This proof-of-concept, published in Journal of Translational Medicine, outlines how CARs built from fragments of Alzheimer’s antibodies can be deployed in mouse immune cells to detect disease-specific protein forms with high precision.
The research taps into the same principles that have driven CAR-T therapies in cancer; however, rather than directing the immune system to kill, the aim here is to train it to heal. Dr Julie Andersen, senior author on the paper, described the motivation: “Current treatments act as a sledgehammer. We aim to develop a targeted scalpel.” With regulatory scrutiny mounting over the side effects of Alzheimer’s antibody drugs – seizures, swelling, brain bleeds – the need for therapies that are both selective and sparing becomes all the more pressing.
Longevity.Technology: The transposition of CAR-based immune engineering from cancer to Alzheimer’s represents more than just cross-pollination between fields – it could herald a shift in how we think about therapeutic precision in the aging brain. Where cancer immunotherapy unleashes cellular killers, this approach co-opts the same scaffolding to create healing agents with target-specific intelligence. With the ability to discriminate between different toxic species of amyloid and tau, the study’s engineered cells aim not to carpet-bomb the brain, but to seek and neutralize pathogenic targets with surgical accuracy. That’s a compelling proposition in a therapeutic landscape still struggling with the blunt-force trauma of side-effect-laden monoclonal antibodies.
This research also signals a maturing moment for cell therapies in neurodegeneration—not just because the concept works in vitro, but because it builds on antibody targets that are already in Phase III. That accelerates the translational clock and will not be lost on investors looking for tractable paths to the clinic. But perhaps the most exciting aspect is the platform’s extensibility: if CARs can be tuned to hunt down extracellular aggregates in Alzheimer’s, then why not in Parkinson’s, or even systemic amyloidoses? Add to that the Buck Institute team’s decision to release the full receptor sequences – an unusually open move in a field often slowed by opacity – and this study becomes more than a promising proof-of-concept. It becomes a strategic gift to the neuroimmunology community and a tantalising glimpse of how adaptive cellular therapies might one day patrol the aging brain – smart, mobile and armed with therapeutic payloads of the future.
Specificity matters
It is a truth universally acknowledged that Alzheimer’s pathology is complex; although amyloid plaques and tau tangles are defining features, they exist in multiple conformations, not all of which are equally toxic. The Buck team’s innovation lies in their attempt to target not merely amyloid beta or tau generically, but specific toxic forms. The study used single-chain variable fragments (scFvs) from well-characterized antibodies including Aducanumab, Lecanemab, Donanemab, Remternetug and E2814 – several of which are either approved or in late-stage clinical trials. These were engineered into CAR constructs and tested in a mouse T cell line as a reproducible screening platform [1].
“We’re showing for the first time that immune cells can be trained to recognize not just amyloid or tau in general – but specific forms of these proteins that are thought to be most toxic,” said lead author Dr Chaska Walton. “It’s a bit like an autonomous taxi – you type in the destination address and the engineered receptor cells end up exactly where you want them to be.”
In experiments, the tau-targeting E2814-CAR responded selectively to tau fibrils, while Adu-CAR and Rem-CAR were particularly effective against aggregated forms of Aβ1-42 and pyroglutamated Aβp3-42, respectively [1]. Not all constructs showed clear activity; Don-CAR, for instance, displayed limited response – possibly due to a lack of membrane expression or reduced affinity for the aggregated Aβ used in the model.
Healing, not harming
Unlike CAR-T cells in oncology, which are designed to destroy their targets, these CAR-engineered immune cells are envisaged as therapeutic allies – capable of identifying disease-specific proteins and delivering treatment locally. Walton hopes to develop cells that act as “mobile biological drug factories” – able to sense pathology, release a therapeutic payload, then move on. The next step will involve engineering cells that not only detect pathology but also carry and release a treatment cargo in vivo.
“It’s important to note that this technology does not involve the same toxicity seen in CAR-T cells,” said Walton. “Those receptor cells are designed to kill cancer cells. Our cells will be designed to heal. We want to save neurons.”
A platform with potential
The implications of this study may reach beyond Alzheimer’s. The authors suggest that CAR technology could, in principle, be applied to any disease involving extracellular protein aggregates – a category that includes Parkinson’s disease and certain rare amyloidoses [1]. If so, these findings open the door to a new class of targeted cell therapies for age-associated conditions that have long resisted treatment.
Indeed, the decision to publish the complete receptor sequences – often held back in patents or redacted from publications – reflects a desire to accelerate progress across the field. “A lot of researchers will test their constructs and report out results, but they won’t give you the complete amino acid sequences to make them,” said Walton. “But the sequences are in our study. They’re there and anyone could use them for their cells, whatever cell type they are, which is the way research should be.”
“In addition to furthering our own research, we see this transparency as a gift to the community,” said Andersen. “Furthering research for everybody is what this team is all about.”
That spirit of openness was echoed by co-author Cynthia Siebrand, who built the panel of CARs used in the study. “It shows that we can harness existing Alzheimer’s antibody knowledge and convert it into a viable, adaptable cell therapy,” she said.
Looking ahead
The concept of cellular therapies that patrol the brain, identify pathology, and deliver treatment on site may still be some years from clinical use – but the direction of travel is clear. If immune engineering can be adapted to the nuanced needs of the aging brain, it will not only change how we treat neurodegenerative disease, but how we think about cellular resilience and longevity itself.
[1] https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06572-6
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