Cerebrovascular Dysfunction in Neurodegenerative Diseases

Cerebrovascular dysfunction is increasingly recognised as a central contributor to the onset and progression of a wide range of neurodegenerative disorders. Disruption of the blood–brain barrier and impairment of neurovascular coupling compromise the tightly regulated exchange of nutrients, metabolites and signalling molecules between the blood and brain. Endothelial cells, pericytes and astrocytic end-feet collectively form the neurovascular unit that maintains capillary integrity, regional blood flow and metabolic support for neurons. In many conditions, including Alzheimer’s disease, amyotrophic lateral sclerosis and frontotemporal dementia, the breakdown of these vascular elements precedes or parallels neuronal degeneration, exacerbating inflammatory and oxidative stress pathways. Hypoperfusion, tight junction disassembly and basement membrane alterations promote the infiltration of peripheral immune factors and toxic protein aggregates, creating a vicious cycle linking vascular impairment to classic pathological hallmarks such as amyloid-β, hyperphosphorylated tau and α-synuclein deposition. Understanding the interplay between vascular health and neurodegeneration offers new avenues for early diagnosis, vascular-targeted therapies and biomarker development with broad implications for reducing the global burden of age-related cognitive decline.

Research from Nature Portfolio

Recent studies have revealed that depletion of the RNA-binding protein TDP-43 in cerebral endothelial cells disrupts core blood–brain barrier pathways across multiple neurodegenerative conditions. Single-nucleus profiling of human cortex identified a disease-associated capillary subset characterised by diminished β-catenin signalling and upregulated inflammatory markers. Experimental TDP-43 loss in endothelial models recapitulates these transcriptional changes and induces barrier breakdown, highlighting a novel mechanism by which endothelial dysfunction accelerates blood–brain barrier failure.

Cerebrovascular Dysfunction in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in cerebrovascular dysfunction in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Blood–brain barrier (BBB): A selective endothelial barrier that controls exchange of substances between the blood and brain.

Neurovascular unit (NVU): The integrated system of endothelial cells, pericytes, astrocytes and neurons that regulates cerebral blood flow.

Endothelial cells: The specialised cells lining cerebral capillaries that form the structural basis of the BBB.

Pericytes: Mural cells embedded in capillary walls that maintain vascular stability and regulate blood flow.

TDP-43: A nuclear RNA-binding protein whose loss in endothelial cells has been linked to barrier dysfunction.

References

1. Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration. Nature Neuroscience (2025).
2. Blood–brain barrier disruption: a pervasive driver and mechanistic link between traumatic brain injury and Alzheimer's disease. Translational Neurodegeneration (2025).
3. Challenges and Future Perspectives in Modeling Neurodegenerative Diseases Using Organ‐on‐a‐Chip Technology. Advanced Science (2024).
4. The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders. Acta Neuropathologica (2024).