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Review
. 2014 Nov 10:6:311.
doi: 10.3389/fnagi.2014.00311. eCollection 2014.

Bioenergetic dysfunction and inflammation in Alzheimer's disease: a possible connection

Heather M Wilkins  1 , Steven M Carl  2 , Alison C S Greenlief  2 , Barry W Festoff  3 , Russell H Swerdlow  4
Affiliations
Review

Bioenergetic dysfunction and inflammation in Alzheimer's disease: a possible connection

Heather M Wilkins et al. Front Aging Neurosci. .

Abstract

Inflammation is observed in Alzheimer's disease (AD) subject brains. Inflammation-relevant genes are increasingly implicated in AD genetic studies, and inflammatory cytokines to some extent even function as peripheral biomarkers. What underlies AD inflammation is unclear, but no "foreign" agent has been implicated. This suggests that internally produced damage-associated molecular pattern (DAMPs) molecules may drive inflammation in AD. A more complete characterization and understanding of AD-relevant DAMPs could advance our understanding of AD and suggest novel therapeutic strategies. In this review, we consider the possibility that mitochondria, intracellular organelles that resemble bacteria in many ways, trigger and maintain chronic inflammation in AD subjects. Data supporting the possible nexus between AD-associated bioenergetic dysfunction are discussed.

Keywords: Alzheimer’s disease; DAMP; bioenergetics; inflammation; mitochondria.

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Figures

Figure 1
Figure 1
Damage-associated molecular pattern signaling mechanisms. Mitochondrial components can induce a DAMP response through the activation of TLR, FPR, RAGE, P2X7, and/or the NALP3 inflammasome. FPR is a GCPR. FPR signaling is mediated through PLC, PIP2, IP3, and DAG. Downstream activation of PKC leads to signaling through MAPK, PI3K, and activation of NFκB and NAPDH oxidase. TLR receptors dimerize with Myd88 and can activate NFκB through RIP1 kinase, MAPK, or PI3K pathways. The TLR pathway also activates NADPH oxidase. RAGE receptor signaling activates PKC and CdC42/Rac (or Ras). Downstream PI3K, MAPK or JNK, and Erk1/2 are activated. This leads to NFκB activation (in addition to SP1 and AP1). P2X7 activation leads to NRLP3 inflammasome signaling. NLRP3 (or IL-1R) activation mediates inflammasome signaling through NLRP3, ACS, and caspase-1 (or RIG-1). Pro-IL-1 is cleaved into IL-1β and IL-1α. NFκB activation initiates transcription of Pro-IL-1, IL-10, IL-18, IL-6, TNFα, along with many other cytokine and chemotactic factors.
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