Alzheimer's disease (AD) is a neurodegenerative disorder that leads to profound cognitive decline and eventually death. There are no effective treatments or preventative measures available, and the incidence and prevalence of the disease are increasing. New insights and tractable therapeutic targets are sorely needed. Genetic evidence indicates that a major cause of AD is the production of the ?-amyloid (A?) peptide. The A? peptide can oligomerize and be deposited as extracellular plaques in the brain and blood vessels, but the mechanism of how it leads to neuronal death is not known. There is increasing evidence of a vascular contribution in AD: patients suffer from brain hypoperfusion, the cerebral vasculature is damaged, and abnormal hemostasis is present. Circulatory deficiencies could therefore play an important role in the pathogenesis of this disease. We have demonstrated an increase in blood brain barrier (BBB) permeability and neurovascular damage in AD mice, and we showed that fibrin(ogen) deposition potentiates these processes. We have also found that A binds to fibrinogen and has a dramatic effect on fibrin clot formation. Clots formed in the presence of A? have an abnormal structure and are resistant to degradation by fibrinolytic enzymes. Therefore, in the presence of A?, any fibrin deposits formed would be more persistent and would exacerbate BBB damage, neuroinflammation, and neuronal death. In keeping with the known genetic interaction between AD and the ApoE genotype, we have also demonstrated that ApoE affects the interaction between fibrinogen and A? and the isoforms differentially influence fibrinogen deposition in the human brain. To further study the role of A? in fibrin clot formation, we will combine in vitro and in vivo techniques to analyze and characterize the interaction between A? and fibrinogen. The role of the various ApoE isoforms in this process will also be examined. Finally, we will examine the effects of fibrinogen deposition on the brain in the absence of A? to deduce the specific contribution of fibrin(ogen) to AD-related pathologies. The proposed experiments will define the role of fibrin(ogen) in AD and could lead to new therapeutic strategies for preventing or retarding progression of the disease.
Alzheimer's disease (AD) affects a large and growing portion of the population and has been studied for over a century, yet there are few available therapies to aid in the loss of cognition and no effective preventative measures. We have found that the buildup of fibrin in the brains of AD mouse models is deleterious and contributes to their cognitive decline. The proposed studies will provide a new way to understand how this disease progresses from the perspective of disrupted blood flow to the brain, which will also explain how the nature of the fibrin clot is altered in the presence of ?-amyloid to allow for this persistence and how other genes can influence progression.
|Singh, Pradeep K; Kawasaki, Masanori; Berk-Rauch, Hanna E et al. (2018) Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks A?-Fibrinogen Interaction and A?-Induced Contact System Activation. Biochemistry 57:1399-1409|
|Yamamoto-Imoto, Hitomi; Zamolodchikov, Daria; Chen, Zu-Lin et al. (2018) A novel detection method of cleaved plasma high-molecular-weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment. Alzheimers Dement (Amst) 10:480-489|
|Strickland, Sidney (2018) Blood will out: vascular contributions to Alzheimer's disease. J Clin Invest 128:556-563|
|Chen, Zu-Lin; Revenko, Alexey S; Singh, Pradeep et al. (2017) Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice. Blood 129:2547-2556|
|Norris, Erin H; Strickland, Sidney (2017) Fibrinogen in the Nervous System: Glia Beware. Neuron 96:951-953|
|Ahn, Hyung J; Chen, Zu-Lin; Zamolodchikov, Daria et al. (2017) Interactions of ?-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer's disease. Curr Opin Hematol 24:427-431|
|Zamolodchikov, Daria; Berk-Rauch, Hanna E; Oren, Deena A et al. (2016) Biochemical and structural analysis of the interaction between ?-amyloid and fibrinogen. Blood 128:1144-51|
|Zamolodchikov, D; Renné, T; Strickland, S (2016) The Alzheimer's disease peptide ?-amyloid promotes thrombin generation through activation of coagulation factor XII. J Thromb Haemost 14:995-1007|
|Yao, Yao; Norris, Erin H; Mason, Christopher E et al. (2016) Laminin regulates PDGFR?(+) cell stemness and muscle development. Nat Commun 7:11415|
|Chung, Y C; Kruyer, A; Yao, Y et al. (2016) Hyperhomocysteinemia exacerbates Alzheimer's disease pathology by way of the ?-amyloid fibrinogen interaction. J Thromb Haemost 14:1442-52|
Showing the most recent 10 out of 28 publications