Fig. 2

Pathological drivers of CCH-associated VCI. Several CCH-induced pathological drivers have been long associated with the pathogenesis of VaD including energy imbalance, inflammation, endoplasmic reticulum (ER) stress, oxidative stress and mitochondrial dysfunction. Decreased ATP production impairs ATPase pumps, results in neuronal depolarization, and leads to a deregulation in the glutamate homeostasis at the synaptic cleft and excitotoxicity in the brain. Low cerebral blood flow triggers the brain to utilize anaerobic respiration to produce ATP and this results in the accumulation of lactate within the neurons, leading to acidosis. Neuronal death following CCH is primarily attributed to the increase in the pro-inflammatory cytokine release during the chronic inflammatory response. Danger associated molecular patterns (DAMPs) released by the brain cells can also trigger glial activation and leukocyte infiltration, both of which can also produce pro-inflammatory cytokines. At the cellular level, increase in the reactive oxidative species from various sources, including the mitochondria, induces the oxidative stress state. While the increase in reactive oxygen species can contribute to the redox dynamics and hemodynamics imbalance, it can also induce chronic ER stress. Persistent ER stress leads to an accumulation of misfolded proteins and can have fatal effects on neuronal survival and integrity via the terminal unfolded protein response (UPR) pathway, as well as contributing to Ca²⁺ homeostatic imbalance. Mitochondrial deterioration causes a further decrease in the ATP production, leading to proteosomal dysfunction, as well as contributing to the frequency of mutagenesis events at the mitochondrial DNA. In a chronic state of CCH, these drivers are pathological and ultimately pave the way for downstream disease mechanisms