Fig. 4

Acute and chronic excitotoxicity and shared mechanisms between ischemic stroke and sporadic AD. The sketch diagram illustrates similarities and differences between ischemic stroke and AD. Both brain disorders suffer from overactivations of eNMDARs that are subjected to regulations by glutamate concentration, expression of NMDAR subunits (e.g. GluN2 and GluN3), and other modulatory mechanisms. The vast and rapid Ca²⁺ influx upon cerebral ischemia and much mild but lasting Ca²⁺ stress in AD trigger distinctive Ca²⁺-dependent signaling pathways, leading to acute and chronic excitotoxicity, respectively. Depending on the severity and region of damage, ischemic stroke causes transient or permanent deficits of locomotor/sensorimotor activities and psychological/psychiatric/cognitive functions. Cerebral ischemia is also known for causing mitochondria dysfunction and ER Ca²⁺ stress that may be responsible for post-stroke AD-like pathology. On the other hand, chronic excitotoxicity in AD is induced by long-lasting small Ca²⁺ increases and deteriorating signaling pathways that lead to synaptic and neural network interruptions in specific regions critical for cognition, followed by Aβ deposition via increased activities of β- and δ-secretases [355]. This chronic excitotoxicity may cause late-onset AD in Aβ-dependent or -independent manner, which remains to be further investigated