Plasminogen Activation Dynamics in Alzheimer's Disease

Plasminogen activation represents a pivotal proteolytic cascade in the central nervous system, in which zymogenic plasminogen is converted to the broad‐spectrum protease plasmin by tissue plasminogen activators. Under physiological conditions, plasmin contributes to clearance of extracellular amyloid‐β peptides, maturation of neurotrophic factors such as brain‐derived neurotrophic factor (BDNF), and maintenance of synaptic plasticity. In Alzheimer’s disease, this balance is perturbed: expression of activators (tPA, urokinase‐type plasminogen activator) may be upregulated or mislocalised, while inhibitors (plasminogen activator inhibitor-1, neuroserpin) accumulate, culminating in reduced plasmin activity. Consequent retention of amyloid plaques, impaired neurotrophin processing and neurovascular unit dysfunction exacerbate neurodegeneration and cognitive decline. Recent models also implicate altered plasmin dynamics in blood–brain barrier permeability and in the interplay between glial cells and neurons. Efforts to quantify ratios of tPA to its inhibitors in peripheral fluids have revealed potential biomarkers reflecting disease severity and progression. Therapeutic strategies targeting restoration of plasminogen activation—either by modulating inhibitor levels or by enhancing activator function—are under active investigation with a view to ameliorating amyloid pathology, supporting synaptic resilience and improving clinical outcomes.

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Plasminogen Activation Dynamics in Alzheimer's Disease publication trend

The graph below shows the total number of articles in plasminogen activation dynamics in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Plasminogen: Inactive precursor of plasmin, circulating in plasma and present in brain interstitial fluid.

Tissue plasminogen activator (tPA): Serine protease that catalyses conversion of plasminogen to plasmin, crucial for extracellular proteolysis.

Plasminogen activator inhibitor-1 (PAI-1): Principal inhibitor of tPA and urokinase, regulating plasmin formation and activity.

Neuroserpin: Neuronal serine protease inhibitor that modulates tPA activity and influences synaptic remodelling.

Brain-derived neurotrophic factor (BDNF): Neurotrophin crucial for neuronal survival and synaptic plasticity, produced as pro-BDNF and activated by plasmin.

Amyloid β (Aβ): Peptide fragments derived from amyloid precursor protein whose aggregation characterises Alzheimer’s pathology.

References

1. Serum PAI-1/BDNF Ratio Is Increased in Alzheimer’s Disease and Correlates with Disease Severity. ACS Omega (2023).
2. Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications. CNS Neuroscience & Therapeutics (2018).
3. Plasminogen Activators in Neurovascular and Neurodegenerative Disorders. International Journal of Molecular Sciences (2021).
4. Activators and inhibitors of the plasminogen system in Alzheimer’s disease. Journal of Cellular and Molecular Medicine (2012).
5. Amyloid β-Protein Stimulates the Expression of Urokinase-type Plasminogen Activator (uPA) and Its Receptor (uPAR) in Human Cerebrovascular Smooth Muscle Cells*. Journal of Biological Chemistry (2003).
6. Alzheimer’s Disease Severity Is Associated with an Imbalance in Serum Levels of Enzymes Regulating Plasmin Synthesis. Pharmaceuticals (2022).
7. The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective. Acta Neurologica Belgica (2023).