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onsdag 7 november 2012

Beeta-amyloidi oligomerisoi fibrinogeeniä

ja stimuloi omaa fibrillien muodostamistaan fibrinogeeni-interaktion  avulla. 
 results indicate that the fibrinogen oligomers are unstable. Therefore, the fibrinogen oligomer might be an intermediate state during the Aβ-induced fibrinogen aggregation process. Fibrinogen deposition with or without conversion to fibrin increases inflammation and vascular permeability where it is deposited (18, 19). Increased levels of fibrinogen alter vascular reactivity and impair endothelial cell layer integrity by binding to endothelial cell membrane receptors (17, 31). Taken together, the Aβ–fibrinogen interaction could reduce fibrin degradation and induce fibrinogen deposition in blood vessels. Both persistent fibrin and fibrinogen oligomer deposits in blood vessels may increase inflammation and cause neurovascular damage.
Protein misfolding and aggregation are hallmarks of several neurodegenerative disorders (32, 33), exemplified by Aβ in AD (1). Our study shows that Aβ can alter the physical properties and induce the aggregation of an entirely different protein (fibrinogen) as well as induce its own fibrillization. Although Aβ42 binds both fibrinogen and FragD, Aβ42 induced oligomerization of only fibrinogen, not FragD. This result indicates that Aβ42 binding itself is not enough to induce oligomerization of a binding partner and that fibrinogen is a specific target for Aβ-induced oligomerization. Fibrinogen has two identical ends (FragDs), and Aβ42 may bind at each. The symmetrical shape of fibrinogen with two binding sites could be the reason why Aβ42 induces oligomerization of only fibrinogen and not FragD.
Overall, the interaction between Aβ and fibrinogen caused fibrinogen oligomerization, promoted fibrin(ogen) deposition, as well as increased Aβ fibrillization. This study, combined with our previous work, suggests that the interaction between Aβ and fibrinogen may be an important contributor to AD pathogenesis. The development of AD therapies has been hampered thus far by the lack of a defined pathological mechanism in AD. Our discovery suggests a unique mechanism for AD and a unique target (fibrinogen) for AD treatment. Molecules that block this pathological interaction could restore the normal structure of the fibrin clot and could be used as therapeutic agents for AD without affecting normal blood clotting.


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