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Alzheimer’s Disease Basic Scientific Article

Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease.

Alzheimer’s disease (AD) is characterized by abnormal senile plaques and neurofibrillary tangle formations.  Amyloid-β peptide (AB) and precursor protein (AβPP) are the major components of these senile plaques.  Aβ is thought to be a major contributor to the neurodegenerative process, acting either through neurotoxic mechanisms or local inflammatory processes.  Interestingly one of the early hallmarks of AD is abnormal cerebral vasculature.  Neurovascular damage can allow fibrinogen access to the CNS.  Fibrinogen, classically known for its role in the clotting cascade, cannot normally cross the BBB.  Fibrin is found in the brains of AD patients, but the pathological significance is unknown.  Fibrin accumulation can be reduced genetically or pharmalogically. 

The aim of the experiment is to measure BBB permeability and fibrin deposition in three mouse models of AD.  Their results demonstrate BBB damage and the presence of fibrin in the brain of AD mice.  Furthermore the tPA/plasmin system, which likely aids in the clearance of Aβ, is down regulated in AD in accord with reductions in other naturally occurring Aβ-degrading proteases.  Also modulation of fibrin levels affects the pathology of AD mice, reducing fibrinolysis, thereby increases fibrin deposits, worsening the pathology, whereas fibrinogen depletion attenuates microgliosis and neurovascular damage.  Decreased clearance of fibrin is also thought to contribute to the progression of Aβ pathology.  The initial insult to the microvasculature likely arises from increased Aβ levels.  Fibrinogen binding elicits activation of NF-KB, caused increased expression of cytokine genes.  Thus fibrin may be an upstream effector of neuroinflammation .  Also fibrin-induced microgliosis could be toxic to endothelial cells.  Fibrin along with the mechanisms involved in its clearance, may present novel therapeutic targets for slowing the progression of AD.

The author’s utilized pharmacological methods to examine fibrin’s role, namely from platelets, in AD mouse models.  The aim was to reduce protein sources, which are linked to senile plaques, in order to prevent or lessen AD.  The data does suggest that this therapy is an effective way of modulating AD in mouse models.  However if this line of therapy was employed in human subjects significant side effects could result.  Humans are far more sensitive to reductions in platelet levels compared to mice.  If human platelet levels were reduced to those of the mice in these studies minor injuries could become life-threatening situations.

Source:  Justin Paul, Sidney Strickland, and Jerry P. Melchor:  Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer ’ s disease, Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065.