Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease

Abstract

Mitochondrial dysfunction and neuroinflammation occur in Alzheimer's disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.

Figure 1. Inflammation induced by mitochondrial-derived DAMP molecules

Mitochondrial-derived DAMPs (including mtDNA, formyl peptides, RNA, ATP, certain mitochondrial-localized proteins, and cardiolipin) activate pattern recognition receptors (PRRs) such as toll-like receptors, formyl peptide receptors, or the NLRP3 inflammasome. Activation of these receptors leads to downstream phosphorylation and activation of p38 MAPK. Activated p38 MAPK can then activate NFκB, inducing its translocation to the nucleus. NFκB facilitates the transcription of cytokines such as TNFα. TNFα can further amplify an inflammatory cascade by independently activating p38 MAPK and NFκB signaling. NFκB may also initiate APP transcription.

Figure 2. Potential bioenergetic medicine approaches

In the brain, OAA activates molecules and pathways that facilitate mitochondrial biogenesis, activates factors that favor cell/tissue growth, enhances insulin signaling, and promotes neurogenesis while countering inflammation. A ketogenic high fat diet favorably affects some parameters that favor mitochondrial biogenesis, counters inflammation, and may increase mtDNA transcription efficiency. Exercise (potentially through lactate for some parameters) activates molecules and pathways that facilitate mitochondrial biogenesis, activates factors that favor cell/tissue growth, and promotes neurogenesis while countering inflammation.

Figure 3

Structure of OAA.