Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease?

Abstract

Recent advances highlight that inflammation is critical to Alzheimer Disease (AD) pathogenesis. Indeed, several diseases characterized by inflammation are considered risk factors for AD, such as type 2 diabetes, obesity, hypertension, and traumatic brain injury. Moreover, allelic variations in genes involved in the inflammatory cascade are risk factors for AD. AD is also characterized by mitochondrial dysfunction, which affects the energy homeostasis of the brain. The role of mitochondrial dysfunction has been characterized mostly in neuronal cells. However, recent data are demonstrating that mitochondrial dysfunction occurs also in inflammatory cells, promoting inflammation and the secretion of pro-inflammatory cytokines, which in turn induce neurodegeneration. In this review, we summarize the recent finding supporting the hypothesis of the inflammatory-amyloid cascade in AD. Moreover, we describe the recent data that demonstrate the link between altered mitochondrial dysfunction and the inflammatory cascade. We focus in summarizing the role of Drp1, which is involved in mitochondrial fission, showing that altered Drp1 activation affects the mitochondrial homeostasis and leads to the activation of the NLRP3 inflammasome, promoting the inflammatory cascade, which in turn aggravates Amyloid beta (Ab) deposition and tau-induced neurodegeneration, showing the relevance of this pro-inflammatory pathway as an early event in AD.

Mitochondria in Alzheimer’s Disease Pathogenesis

“…Interactions between Drp1 and Aβ induce synaptic loss [195,196]. The Drp1 inhibitor, mitochondria division inhibitor 1 (Mdivi1), a quinazolinone derivative, has been found to effectively target synaptic depression that occurs due to Aβ in AD [197,198]. Mdivi1 has been found to specifically target mitochondrial dysfunction by attenuating ROS production and enhancing ATP production [199].…”

“…Maintains mitochondrial membrane potential. [191][192][193] Mdivi1 ↓ in the fission proteins Drp1 and Fis1, ↑ in the fusion proteins Mfn1 and Mfn2, ↓ excessive fragmentation of mitochondria, inhibition of Aβ-DRP1 complex formation [197][198][199][200][201] Nicotinamide compounds: nicotinamide mononucleoside, nicotinamide mononucleotide, nicotinamide riboside ↓ DNA damage, ↓ neuroinflammation, and ↓apoptosis of hippocampal neurons [209] Abbreviations: Aβ-amyloid β; DRP1-dynamin-1-related protein 1; Mdivi1-mitochondria division inhibitor 1; Mfn-mitofusin; MitoQ-mitoquinone mesylate; NADPH-nicotinamide adenine dinucleotide phosphate; ROS-reactive oxygen species; SkQ1-plastoquinonyl decyl triphenylphosphonium; ↑-increased; ↓-decreased.…”