Question

As cells die from hypoxia, ROS, and stress, they release ATP and DAMPS, which activate purinergic and pattern receptors on microglia. ATP activates P2X7 receptors, and causes microglia to release pro-inflammatory cytokines. DAMPS also activate toll-like receptors and the CD36 cell-surface protein receptor. CD36 stimulates an increase in NF-kB dependent inflammatory cytokine and chemokines, which causes the cell to deteriorate further. CD36 expression increases in the post-ischemic brain and increases injury size. CD36 plays an essential role in clearing apoptotic cell bodies by phagocytosis. CD36 also facilitates the transfer of long chain fatty acids across the plasma membrane. Hypoxia causes the translocation of CD36 to the plasma membrane, resulting in intracellular lipid accumulation; this contributes to ischemia-reperfusion and poor ischemic outcomes.

Answer 1

Glutamate release following brain injury or ischemia triggers excitotoxicity through overactivation of NMDA receptors, leading to calcium influx and neuron damage. Excessive calcium triggers cellular processes that result in ROS production, mitochondrial disruption, and apoptosis. The upregulation of CD36 exacerbates inflammation, contributing to further injury while also facilitating phagocytosis of dead cells.

Step-by-step explanation:

The release of glutamate into the extracellular space following injury or ischemia leads to the activation of glutamate receptors, especially NMDA receptors, which then permit an excess influx of calcium ions into neurons. The presence of a magnesium ion normally blocks these receptors, preventing excessive calcium entry. However, the loss of this blockade under pathologic conditions such as hypoxia allows for uncontrolled activation, contributing to neuronal excitotoxicity and cell death. This calcium overload activates various damaging pathways, including the mitochondrial permeability transition pore, causing the release of reactive oxygen species (ROS) and exacerbating apoptosis.

Excess intracellular calcium disrupts homeostasis further by halting ATP production, which is necessary for maintaining the electrochemical gradients across cell membranes and the functioning of glutamate transporters. These transporters normally clear glutamate from synapses, but their shutdown results in glutamate accumulation, potentiating excitotoxic damage. Prolonged exposure to glutamate and increased intracellular calcium not only affects neurons but also oligodendrocytes, which provide myelination, thus amplifying central nervous system (CNS) injury.

The role of CD36, a cell-surface protein that facilitates the transfer of long-chain fatty acids, becomes upregulated in ischemic brain conditions, promoting inflammation and neuronal injury, yet also playing a part in phagocytosis of apoptotic cells. These mechanisms highlight the complex interplay of signaling pathways and cellular responses that contribute to the progression and exacerbation of brain injuries, and also apply to chronic neurodegenerative diseases like Alzheimer's Disease.