Excitotoxicity-induced Endocytosis As A Potential Target For Stroke Neuroprotection Part 1

Decreased neuronal survival-signaling and brain damage: Stroke is a leading cause of death worldwide, the major cause of adult disability, and second of dementia. Despite the social and economic importance of this disorder, and after intense research, no effective drugs have yet reached the clinic. 

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Blood reperfusion with the thrombolytic agent tissue plasminogen activator remains the only pharmacologic treatment currently available for ischemic stroke, the major type of brain infarction (> 85% of total cases). 

Damage in this situation results from thrombotic or embolic occlusion of a cerebral artery causing a decrease of blood flow to a specific area of the brain parenchyma, neurons being particularly sensitive to a reduction of the supply of glucose and oxygen. 

It is thus a priority to develop neuroprotective strategies able to preserve neurons from ischemic injury and, in this way, reduce brain damage and patient disability. A promising approach involves the rescue of the area of the penumbra surrounding the infarct, a region functionally silent but structurally intact. 

However, neurons in the penumbra can undergo a process of delayed death known as excitotoxicity, caused by overstimulation of the N-methylD-aspartate type of excitatory glutamate receptors (NMDARs). 

The critical role played by these receptors in synaptic plasticity, learning, and memory, together with dual functions in neuronal survival and death (Hardingham et al., 2002), underlies the previous failure of NMDAR blockade as a therapeutic target in stroke. 

Nevertheless, the low-affinity uncompetitive NMDAR antagonist memantine is still able to improve cognitive functions and behavioral disturbances in moderate-to-severe Alzheimer's disease, a neurodegenerative disorder also associated with excitotoxicity. 

Anyhow, for stroke treatment, we are currently exploring alternative strategies such as the inhibition of neurotoxic proteins that act downstream overactivated NMDARs or directed to enhance neuronal survival pathways. 

Concerning the latter, several laboratories have chosen to analyze the promotion of neurotrophin-dependent survival pathways by treatment with brain-derived neurotrophic factor (BDNF) as a possible strategy for neuroprotection in stroke but also other acute or chronic disorders of the central nervous system. However, a potential caveat of this approach is that signaling mediated by BDNF is dramatically subverted by excitotoxicity, a process not only central to stroke but, as mentioned, also associated with many other neurological disorders (Tejeda and Diaz-Guerra, 2017). 

In models of stroke and human samples, excitotoxicity induces transcriptional and proteolytic mechanisms strongly associated with neurodegeneration that alter the expression of the two major brain isoforms of the BDNF receptor, tropomyosin-related kinase B (TrkB): the catalytically active full-length receptor (TrkB-FL) and a truncated receptor lacking the tyrosine kinase domain (TrkB-T1) (Vidaurre et al., 2012; Tejeda et al., 2016). 

Nonetheless, recent work from my group has demonstrated that it is possible to interfere with TrkB-FL degradation in stroke and, in this way, decrease neuronal death and brain damage (Tejeda et al., 2019). Interestingly, these results have been accomplished by primarily preventing TrkB-FL endocytosis, which is strongly induced by excitotoxicity and precedes receptor processing (Figure 1). 

In this perspective, we will discuss the prospects of using the modulation of excitotoxicity-induced endocytosis, and the subsequent preservation of membrane survival proteins, as a neuroprotective therapeutic strategy for acute brain insults (stroke, epilepsy, or trauma) and excitotoxicity-associated chronic disorders (e.g., Alzheimer's, Parkinson´s, Huntington´s diseases).

Dual role of endocytosis in neuronal survival and death: Endocytosis is a ubiquitous physiological process that mediates nutrient uptake, receptor internalization, and signaling, and essential events for cell growth and survival. 

In neurons, endocytosis is required at the synaptic cleft after neurotransmitter release for recycling of membranes and surface proteins. Meanwhile, in the postsynaptic membranes of glutaminergic neurons, endocytosis is central for the reduction in long-term depression of surface glutamate receptors, mostly of the α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid family. 

NMDARs also undergo internalization in response to ligand binding, synapse maturation, or long-term depression. While C-terminal sequences of GluN2A/B subunits direct endocytosed NMDARs to recycling endosomes, conserved motifs near the juxtamembrane region of GluN1 and GluN2A/B drive receptors to late endosomes and degradation (Scott et al., 2004). 

Notably, trafficking of TrkB isoforms is similarly very important for neurotrophin signaling in physiological conditions. Upon BDNF binding, both isoforms are rapidly and efficiently internalized in a clathrin-dependent way and form signaling endosomes. 

However, while TrkB-T1 predominantly recycles back to the cell surface by a default mechanism, TrkB-FL recycling is less efficient, relies on its tyrosine kinase activity, and is regulated by binding of the protein Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) to a receptor juxtamembrane region located between the transmembrane and tyrosine kinase domains (Huang et al., 2009). 

In addition, endocytosis plays an evolutionarily conserved function in cell destruction by necrosis, a form of death central to stroke and other diseases affecting the central nervous system (Troulinaki and Tavernarakis, 2012). 

A transient upregulation of the endocytic Perspective Margarita Díaz-Guerra* activity has been observed early after cell death induction which is related to changes in calcium homeostasis taking place along neurodegeneration. 

The NMDARs are efficient calcium channels and their overactivation, among other mechanisms, profoundly alters the intracellular regulation of this ion. Correspondingly, endocytosis is enhanced in excitotoxicity by a clathrin/dynamin-mediated mechanism that precedes neuronal death in vitro or in models of ischemia, where stressed but viable neurons of the ischemic region have been described as highly endocytic (Vaslin et al., 2009). 

A crosstalk between endocytosis and the activation by Ca2+ of the protease calpain has been also described. After NMDAR overstimulation, cleavage by calpain of different substrates triggers multiple mechanisms of neurotoxicity, particularly enhancement of calcium overload, disruption of cell structure, and promotion of cell-death signaling by degradation of antiapoptotic proteins or those involved in neuroprotective signaling such as TrkB-FL (Vidaurre at al., 2012). 

The subcellular localization of calpain activation is currently under discussion. Activation is favored near plasma and endosomal membranes but can also occur in microdomains with high local [Ca2+] as well as other cell compartments (mitochondria, nucleus, or Golgi membranes). 

Notably, several components of the clathrin-coated vesicles, including the αand β2-subunits of the adaptor protein complex 2 (AP-2), are calpain substrates and result in hydrolyzed in experimental ischemia and the brain of Alzheimer's disease patients (Rudinskiy et al., 2009). Cleavage of these AP-2 proteins has been suggested to be a mechanism to reduce clathrin-coated vesicles and moderate endocytosis at late stages of necrotic cell death.

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