Is the plasminogen system a link between head trauma and the increased risk of dementia?
Individuals who have sustained brain trauma have a 2-13.5 fold increased risk of developing Alzheimer disease (AD), Frontotemporal dementia, Lewy body dementia and Chronic Traumatic Encephalopathy or Dementia Pugilistica.
Plasminogen is an enzyme that is activated yield plasmin which degrades blood clots in the circulation. In the brain, plasmin facilitates the clearance of amyloid-beta plaques. Plasmin activity is reduced in the brains of AD patients, which may be the reason for the extensive accumulation of amyloid-beta. Accordingly, compounds that increase plasmin activity minimise amyloid-beta pathology in mice with AD. Plasminogen activation is also down-regulated in the presence of alpha-synuclein, a protein that accumulates in Lewy bodies, a pathological feature of Lewy Body Dementias.
Aggregation of proteins including amyloid-beta, alpha synuclein, Tau and TDP-43 are a pathological hallmark of the aforementioned dementias. We have shown that trauma rapidly induces protein aggregation in mice and humans, and these aggregates are not efficiently cleared in plasminogen deficient (plasminogen -/-) mice. Dr Sashindranath hypothesise that a reduction in plasmin activity causes increased aggregation of amyloid-β, alpha synuclein, Tau and TDP-43, which can accelerate dementia-related pathology after trauma. If so, compounds that increase plasmin activation in the brain may aid in preventing dementia after head trauma.
Dr Sashindranath is a Research Fellow based in the Faculty of Medicine, Nursing & Health Sciences at Monash University.