Bioenergetic Dysfunction and Inflammation in Alzheimer’s Disease: A Possible Connection

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.

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

“…Numerous inflammatory pathways appear activated in AD brains, and interestingly elevated cytokines are observed both within AD subject brain tissue and patient sera [11, 16, 18, 21, 22]. Inflammatory signals classically initiate in response to a pathogen, or “foreign” agent.…”

“…It is increasingly recognized that mitochondrial dysfunction and inflammation are interdependent lesions [11, 13]. Overall, though, the underlying cause(s) of these changes are poorly understood.…”

“…Moreover, mitochondrial dysfunction induces inflammation, while the converse, inflammation results in mitochondrial dysfunction, is also true [11, 13–15]. In either case, bioenergetic failure may ultimately result, and combinations of mitochondrial dysfunction, neuroinflammation, and bioenergetic failure may contribute to the development or progression of neurodegeneration and neurodegenerative diseases such as AD [11, 13]. Approaches that target mitochondrial dysfunction, neuroinflammation, or both may, therefore, ultimately prove beneficial for the treatment of AD.…”

Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics

“…Patients may be subjected to the Mini-Mental Status Examination (MMSE) if their clinician suspects abnormal cognitive performance. Pathologically, AD is a diverse and complex disease affecting nearly every subcellular system of the affected neurons (Oddo 2008;Tu et al 2014;Moh et al 2011;Wilkins et al 2014). One primary pathological characteristic has been identified as being an accumulation of amyloid-beta 1-40 and 1-42 (Aβ 1-40 and Aβ 1-42 ) though the primary amyloidogenic product implicated in AD has been Aβ 1-42 (Glabe 2001;Walsh and Selkoe 2004).…”

INPP5D rs35349669 polymorphism with late-onset Alzheimer's disease: A replication study and meta-analysis

“…INPP5D , mainly expressed in hematopoietic cells, plays an important role in a series of inflammatory responses [8]. It has also reported that INPP5D was implicated in the pathogenesis of LOAD through the regulation of microglial cell function [8, 9]. Recently, INPP5D rs35349669 polymorphism was recognized to be strongly associated with the development of LOAD in 74,046 Caucasians [10].…”