Amyloid-β Triggers the Release of Neuronal Hexokinase 1 from Mitochondria

Abstract

Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

“…Because studies suggest that PARP activation plays an important role in many pathophysiological states, including stroke, PD, and AD (3)(4)(5), it is likely that PARPdependent HK inhibition plays a role in the pathophysiology of these disorders. In support of this notion, redistribution and a decrease in HK activity has been shown to play a critical role in oxidative stress and neurodegeneration in AD (31). Similarly, overexpression of HK protects against neurodegeneration in mouse models of PD (32).…”

Alzheimer’s disease and insulin resistance: translating basic science into clinical applications

“…Oligomer actions are thought to underlie other aspects of brain dysfunction in AD, activating signaling pathways that lead to abnormal tau phosphorylation (50)(51)(52) and oxidative stress (53)(54)(55), both hallmarks of AD pathology. Thus, altered neuronal IR function is an important aspect of the overall synaptic and neuronal pathology induced by Aβ oligomers.…”

“…Interestingly, Aβ oligomer-induced neuronal oxidative stress (53,54,74) is blocked by insulin (16,75). The mechanism of protection by insulin appears to involve activation of AKT (75) and prevention of abnormal NMDA receptor (NMDA-R) activation (76).…”

“…These studies will hopefully demonstrate a benefit for AD therapeutics targeting insulin signaling to treat this devastating disease. (11,54) and, possibly, PKR and IKK pathways. Activation of these stress-sensitive kinases, which can also be triggered by ER stress in peripheral tissues (69), results in IRS-1pSer, decreasing downstream insulin signaling (11,31,54).…”

Energy Metabolism in Huntington’s Disease

“…This whole process concomitantly generates local ADP which is important as a recycling mechanism. Important to note that hexokinase activity in neurons and in other cell types also participates in various essential processes including ATP production, apoptosis, controlling glutathione levels, and preventing neuronal oxidative unbalance (Saraiva et al, 2010). In the brain, HK-1 is the major expressed enzyme isoform.…”