Biology subjects

Bergo, N. J.

Publications and source records attributed to Bergo, N. J..

3 recordsLinked to original sources

bioRxiv2025

Chimeric Antigen Receptors Discriminate Between Tau and Distinct Amyloid-Beta Species

Abstract/SummaryThe lack of a definitive cure for Alzheimers disease (AD) is fueling the search for innovative therapeutic strategies. Having revolutionized cancer immunotherapy, immune cell engineering with chimeric antigen receptors (CAR) is being explored to target AD. Whether CARs can recognize distinct amyloid-{beta} (A{beta}) species and tau neurofibrillary tangles (NFTs)--hallmark pathologies of AD--remains unclear. To investigate this, we engineered CARs based on AD antibodies targeting tau (E2814), A{beta} (Lecanemab and Aducanumab), and truncated pyroglutamate form of A{beta} (A{beta}p3-42; Donanemab and Remternetug). To evaluate CAR function, we established the murine DO11.10 hybridoma T-cell line as a practical and scalable testing platform. Our findings demonstrate that CARs can detect and discriminate between tau preformed fibrils (PFFs), A{beta}1-42, and A{beta}p3-42 aggregates. This highlights the potential of repurposing AD antibodies for CAR-based therapies to selectively target tau NFTs and distinct forms of A{beta} senile plaques.

synthetic biology↗

bioRxiv2025

A Human Neuron Alzheimer's Disease Model Reveals Barriers to Senolytic Translatability

Therapeutic successes in mouse models of Alzheimers disease (AD) largely fail to translate into clinical trials, with experimental drugs rarely validated in human models before being administered to humans. To address this, we developed an accessible method for long-term culture of commercially available primary human neurons and astrocytes, along with an amyloid-beta 1-42 (A{beta})-based in vitro AD model. Using this system, we evaluated two senolytic regimens previously shown to be effective in AD mouse models--Navitoclax and Dasatinib plus Quercetin (DQ)--and the natural killer cell line NK92 for emerging immune-mediated senescent cell ablation therapies. NK92 cells preferentially--but not exclusively--targeted A{beta}-treated neurons and astrocytes with senescent-like phenotypes. DQ demonstrated a safe profile for human neurons, but Navitoclax exhibited non-selective neurotoxicity. These findings highlight risks of Navitoclax and NK-based interventions and underscore the critical need for human-relevant models in the AD drug-development pipeline to improve safety and clinical translatability.

neuroscience↗

bioRxiv2024

Aβ-targeting synNotch Receptor for Alzheimer's Disease: Expanding Applications to Extracellular Protein Aggregates

The synthetic Notch receptor (synNotch) system is a versatile platform that induces gene transcription in response to extracellular signals. However, its application has been largely confined to membrane-bound targets due to specific activation requirements. Whether synNotch can also target extracellular protein aggregates, such as amyloid beta (A{beta}) in Alzheimers disease (AD), is unclear. To address this, we engineered an A{beta}-targeting synNotch receptor controlling the production of chimeric human-mouse versions of Lecanemab (Leqembi(R)) or Aducanumab (Aduhelm(R)), both FDA-approved antibodies for AD. We demonstrate that NIH 3T3 cells expressing this synNotch system detect and respond to extracellular A{beta} aggregates by synthesizing and secreting Aducanumab or Lecanemab. These findings broaden the potential applications of synNotch, extending its targets beyond membrane-bound proteins to extracellular protein aggregates, providing obvious benefits to research in this scientific arena.

synthetic biology↗