The brain, a biological engineering wonder, depends on a delicately balanced system of cells, signals, and defense barriers to work in harmony. For decades, researchers have studied neurodegenerative diseases like Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) with a near-exclusive focus on neurons, the brain’s information processors. However, what if the earliest signs of damage occur not within neurons, but in the blood vessels that support and protect them?
In two recent studies conducted in the Patrick Murphy Lab at the University of Connecticut School of Medicine titled “Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects” published in Science Advances and “Endothelial TDP-43 depletion disrupts core blood – brain barrier pathways in neurodegeneration” published in Nature Neuroscience, Omar M. Omar and I (Ashok Cheemala) revealed a surprising and critical role for the brain’s vascular system in neurodegeneration. Our research focuses on TDP-43, a protein already well established in the context of ALS and FTD, but now shown to play an essential role in endothelial cells, which aid in the formation of the blood-brain barrier (BBB).
The blood-brain barrier functions as a gatekeeper, regulating what can enter and leave the internal environment of the brain. When TDP-43 is mutated or missing in these endothelial cells, the integrity of the barrier is compromised. This breach allows molecules normally kept out to penetrate the brain, initiating a cascade of harmful effects. In mouse models, we observed that targeted endothelial disruption of TDP-43 resulted in BBB leakage, glial cell activation – an early sign of brain inflammation – and phospho-Tau accumulation, a hallmark of Alzheimer’s disease pathology. Remarkably, all these changes were noted prior to the initiation of neuronal death or dysfunction, which indicates that vascular compromise may be an initiating event and not a secondary consequence of neurodegeneration.
To determine whether similar patterns exist in human brains, we analysed postmortem brain tissue from individuals diagnosed with ALS, FTD, and Alzheimer’s disease. Our findings confirmed the presence of a distinct population of brain capillary endothelial cells that had reduced nuclear TDP-43. This correlated with reduced Wnt/β‑catenin signalling and increased inflammatory activity through NF-κB pathways in the same cells – molecular signatures that closely mirrored what we observed in the mouse models.
This dual approach, combining human data with controlled animal experiments, provides compelling evidence that endothelial TDP-43 dysfunction is not merely an incidental finding, but a conserved and potentially central mechanism in these diseases.
The implications are significant: if the breakdown of the blood-brain barrier occurs early and drives disease progression, then therapeutic strategies should not only aim to rescue neurons but also protect or restore vascular integrity.
Our findings challenge the traditional neuron-centric model of neurodegeneration and bring the spotlight to the neurovascular unit as a whole.
Understanding how blood vessels interact with and influence brain health opens up new therapeutic windows and encourages a more integrated approach to studying and treating these diseases.
Independent researchers in the field agree that this line of investigation has the potential to change the way we tackle diagnostics and interventions, particularly in the early phases of disease, when the blood-brain barrier is only starting to break down.
While the path from discovery to treatment continues, these results highlight the necessity of considering beyond neurons to see the complete picture of neurodegenerative disease. By revealing the vulnerability and significance of the brain’s vascular foundations, this research offers a new direction in the search for solutions to some of the most challenging conditions of our time.
At the request of IndiaBioscience (specifically Moumita), I am sharing a brief overview of my academic and personal journey.
I was brought up in a small village of Andhra Pradesh, India, by physically disabled parents whose tenacity motivated me to contribute back to society. Despite financial hardships, I excelled academically, topping both my Bachelor’s and Master’s programmes, and pursued my Ph.D. at Pondicherry University, often funding my research from my stipend.
My academic journey started in the field of cancer biology, which later branched into RNA biology during my postdoctoral work at the Indian Institute of Science Education and Research Bhopal (IISER Bhopal). Presently, at UConn Health, I investigate the role of TDP-43 dysfunction in endothelial cells in neurodegenerative diseases such as ALS, FTD, and Alzheimer’s.
Led by a passion for science and mentoring, I strive to make contributions to research as well as to empowering underrepresented groups within academia.