Neuroserpin Pathology in Neurodegenerative Disorders

Neuroserpin is a brain-specific serine protease inhibitor that plays a central role in maintaining neural homeostasis through the regulation of extracellular proteolysis. Under physiological conditions, neuroserpin controls the activity of tissue-type plasminogen activator (tPA), modulating synaptic plasticity, neuronal survival and axonal growth. Mutations or dysregulation of neuroserpin give rise to conformational changes and polymer formation that accumulate within the endoplasmic reticulum, leading to familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare autosomal dementia. Beyond inherited serpinopathies, altered neuroserpin expression has been implicated in common neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, where an imbalance in protease–antiprotease activity contributes to protein aggregation, blood–brain barrier breakdown and neuroinflammation. Loss of neuroserpin exaggerates tPA-mediated excitotoxicity and microglial activation after ischaemic injury, whereas exogenous administration can preserve barrier integrity and extend the therapeutic window for thrombolysis. Proteostasis networks, including endoplasmic reticulum-associated degradation and molecular chaperones, are critical in handling both wild-type and mutant neuroserpin. Advances in region-specific proteomic profiling have begun to reveal the broader impact of neuroserpin deficiency across cortical, cerebellar and retinal circuits, highlighting its neuroprotective and regulatory functions. Collectively, these findings underscore neuroserpin’s dual role as a guardian against proteolytic overactivity and a potential target for therapeutic intervention in a range of neurodegenerative settings.

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Neuroserpin Pathology in Neurodegenerative Disorders publication trend

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

Technical terms

Neuroserpin: Neuronally expressed serine protease inhibitor that regulates extracellular proteolysis by inhibiting tPA and plasmin.

Tissue-type plasminogen activator (tPA): A serine protease involved in fibrinolysis and neuronal plasticity, tightly controlled by neuroserpin.

Familial encephalopathy with neuroserpin inclusion bodies (FENIB): An autosomal dominant dementia caused by mutant neuroserpin polymerisation and intracellular inclusion formation.

Extracellular vesicles (EVs): Membrane-bound particles released by cells carrying proteins and nucleic acids that mediate intercellular communication.

Quantitative proteomics: High-throughput mass spectrometry methods for measuring protein abundance and post-translational modifications across tissues.

References

1. Neuroserpin: structure, function, physiology and pathology. Cellular and Molecular Life Sciences (2021).
2. Neuroserpin, a Brain-associated Inhibitor of Tissue Plasminogen Activator Is Localized Primarily in Neurons IMPLICATIONS FOR THE REGULATION OF MOTOR LEARNING AND NEURONAL SURVIVAL*. Journal of Biological Chemistry (1997).
3. The Axonally Secreted Serine Proteinase Inhibitor, Neuroserpin, Inhibits Plasminogen Activators and Plasmin but Not Thrombin*. Journal of Biological Chemistry (1998).
4. Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum*. Journal of Biological Chemistry (2004).
5. Neuroserpin and Extracellular Vesicles in Ischemic Stroke: Partners in Neuroprotection?. Aging and Disease (2024).
6. Deficiency in Serine Protease Inhibitor Neuroserpin Exacerbates Ischemic Brain Injury by Increased Postischemic Inflammation. PLOS ONE (2013).
7. Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke. Circulation (2002).
8. The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin*. Journal of Biological Chemistry (2011).
9. Quantitative Proteomics Reveal Region-Specific Alterations in Neuroserpin-Deficient Mouse Brain and Retina: Insights into Serpini1 Function. Proteomes (2024).