Platelets Recognize Brain-Specific Glycolipid Structures, Respond to Neurovascular Damage and Promote Neuroinflammation

Abstract

Platelets respond to vascular damage and contribute to inflammation, but their role in the neurodegenerative diseases is unknown. We found that the systemic administration of brain lipid rafts induced a massive platelet activation and degranulation resulting in a life-threatening anaphylactic-like response in mice. Platelets were engaged by the sialated glycosphingolipids (gangliosides) integrated in the rigid structures of astroglial and neuronal lipid rafts. The brain-abundant gangliosides GT1b and GQ1b were specifically recognized by the platelets and this recognition involved multiple receptors with P-selectin (CD62P) playing the central role. During the neuroinflammation, platelets accumulated in the central nervous system parenchyma, acquired an activated phenotype and secreted proinflammatory factors, thereby triggering immune response cascades. This study determines a new role of platelets which directly recognize a neuronal damage and communicate with the cells of the immune system in the pathogenesis of neurodegenerative diseases.

Glatiramer Acetate (Copaxone) Modulates Platelet Activation and Inhibits Thrombin-Induced Calcium Influx: Possible Role of Copaxone in Targeting Platelets during Autoimmune Neuroinflammation

“…One of the commonly used rodent models to test the platelet functions in vivo is the tail bleeding test [22]. If the activation of platelets is inhibited, bleeding time increases as we described in our previous study [11]. Indeed we found that i.v.…”

“…It was also demonstrated that GA may cause specific symptoms such as chest pain, flushing, dyspnea, and anxiety [24]. As we demonstrated previously in mouse model, dyspnea and restless behavior are both associated with massive platelet activation/degranulation and associated with the release of potent mediators from platelets such as histamine [11]. Other investigators found that in humans massive platelet activation/degranulatuion is caused by the administration of radiographic contrast media into blood vessels, indicating that human platelets may degranulate in response to the injection of chemical substances [25].…”

“…We and others have found that depletion of platelets ameliorated neuroinflammation in animal model of MS [10], [11]. It was also proposed that platelets could interact with macrophages and promote their activation and migration to the site of inflammation [20], [21].…”

“…Previously we found that platelets substantially contributed to neuroinflammation in the EAE model [11]. Giving the fact that GA effectively suppressed EAE [12], one potential mechanism of GA action on reduction of EAE severity and possibly MS is by decreasing platelet activation and their communication with leukocytes.…”

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

“…These data already suggested an immune mediated role for platelet contribution in MS, but were then largely forgotten in future generations of MS researchers. Indeed, current studies suggest that platelet depletion reduces disease severity and inflammation in mice that were subjected to experimental autoimmune encephalomyelitis (EAE), a classical animal model of CNS inflammation to study the pathogenesis of MS [30,31,32]. In particular, a number of studies have demonstrated that platelets are present along with an increased activation status in the peripheral blood and in plaques of MS patients as indicated by elevated PMP levels, P-selectin expression (also known as CD62P), increased levels of platelet-activating factor (PAF) and upregulation of GpIIb receptor (see Figure 1) [30,33,34,35,36].…”