The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction

Abstract

Alzheimer’s dementia is a devastating and incurable disease afflicting over 35 million people worldwide. Amyloid-β (Aβ), a key pathogenic factor in this disease, has potent cerebrovascular effects that contribute to brain dysfunction underlying dementia by limiting the delivery of oxygen and glucose to the working brain. However, the downstream pathways responsible for the vascular alterations remain unclear. Here we report that the cerebrovascular dysfunction induced by Aβ is mediated by DNA damage caused by vascular oxidative–nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase. The resulting increase in ADP ribose opens transient receptor potential melastatin-2 (TRPM2) channels in endothelial cells leading to intracellular Ca2+ overload and endothelial dysfunction. The findings provide evidence for a previously unrecognized mechanism by which Aβ impairs neurovascular regulation and suggest that TRPM2 channels are a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer’s dementia and related pathologies.

The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment

“…This hypoactivity could be the result of A␤-derived disturbances in muscular function (Mukhamedyarov et al, 2014). Indeed, A␤ peptides are elevated in skeletal muscles of AD patients (Kuo et al, 2000), where they have been suggested to cause membrane depolarization in fibers by inhibiting the Na ϩ /K ϩ -ATPase and by forming membrane pores (Mukhamedyarov et al, 2011(Mukhamedyarov et al, , 2014. Moreover, A␤ oligomers have been detected in the muscle fibers of sporadic inclusion body myositis patients (Nogalska et al, 2010).…”

“…Indeed, A␤ peptides are elevated in skeletal muscles of AD patients (Kuo et al, 2000), where they have been suggested to cause membrane depolarization in fibers by inhibiting the Na ϩ /K ϩ -ATPase and by forming membrane pores (Mukhamedyarov et al, 2011(Mukhamedyarov et al, , 2014. Moreover, A␤ oligomers have been detected in the muscle fibers of sporadic inclusion body myositis patients (Nogalska et al, 2010). TRPM2 expression in skeletal muscles is low (Fonfria et al, 2006a), which might explain the lack of improvement in AD-related hypoactivity.…”

“…Although ablation of TRPM2 channels improved many AD pathology hallmarks in APP/PS1 mice, it did not improve the hypoactivity phenotype. This hypoactivity could be the result of A␤-derived disturbances in muscular function (Mukhamedyarov et al, 2014). Indeed, A␤ peptides are elevated in skeletal muscles of AD patients (Kuo et al, 2000), where they have been suggested to cause membrane depolarization in fibers by inhibiting the Na ϩ /K ϩ -ATPase and by forming membrane pores (Mukhamedyarov et al, 2011(Mukhamedyarov et al, , 2014.…”

“…It is important to mention that several distinct genetic manipulations in mice have shown promising effects on the toxicity of A␤ peptides or levels of APP metabolites (Lambert et al, 1998;Ohno et al, 2006;Matus et al, 2011;Ma et al, 2013;Jiang et al, 2014). Not all manipulations are expected to lead to therapeutic strategies in humans due to potential experimental limitations.…”

“…We tested the expression of genes previously linked to NMDAR/A␤O excitotoxicity in the hippocampus of controls and TRPM2 Ϫ/Ϫ mice. For NMDAR subunits, we limited our analysis to GluN1, GluN2A, and GluN2B, the most highly expressed subtypes in the adult hippocampus and cortex (Monyer et al, 1994). We also measured transcript levels of the AMPAR subunit GluA2, inclusion of which renders AMPARs Ca 2ϩ -impermeable, and of genes implicated in Ca 2ϩ dysregulation in AD (Demuro et al, 2010), including the ␣7 nicotinic acetylcholine receptor and L-type voltage-gated Ca 2ϩ channels (Ca V 1.2).…”