Mitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer's Disease Blood

Abstract

Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.

Prediction of Mild Cognitive Impairment that Evolves into Alzheimer's Disease Dementia within Two Years using a Gene Expression Signature in Blood: A Pilot Study

“…This suggests that these processes not only are affected in brain tissue but also are reflected in a systemic response that can be detected using gene expression in blood. This is also well in agreement with similar findings in previous AD studies [34][35][36][37][38]. The results also support the concept of AD as a multifactorial sporadic disorder [54] with multiple genes and alterations in gene expression involved [55,56].…”

“…This test detects the blood-based gene expression signature in blood samples and adopts a combination of multiple gene expression assays to obtain a prediction value for disease classification. Alterations in a gene expression signature in peripheral blood are postulated as a result of a systemic disease response in AD as verified by many previous studies [34][35][36][37][38].…”

High-Intensity Interval Exercise and Cerebrovascular Health: Curiosity, Cause, and Consequence

“…Indeed, hyperglycemia and diabetes are important risk factors for dementia, 60 and systemic low-grade chronic inflammation is evident in populations with mild cognitive impairment and Alzheimer's disease. 61 Numerous exercise training studies, including those using models of HIT (discussed next), have shown the efficacy of exercise as a tool to lower blood glucose levels, improve insulin sensitivity, and overall glycemic control, as well as reduce neuro-inflammation (see Figure 1). …”

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

“…This finding should not be construed as specific to mitochondria, as global downregulation of ribosomal gene transcription may occur nonspecifically during extreme biological conditions such as septic shock [17,62]. Similar downregulation of MRPs has been previously described in blood and brain tissue from patients with Alzheimer's disease [14].…”

“…Mitochondrial dysfunction in blood cells has been associated with severity of illness, organ dysfunction, mortality, and immunoparalysis in human sepsis [8][9][10][11][12], including children [13]. Differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism [14][15][16], and injection of endotoxin has been shown to cause widespread suppression of genes encoding for mitochondrial ATP production and protein synthesis within human leukocytes [17]. However, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis.…”