Neuroinflammation in Alzheimer's disease

Abstract

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…This agrees with earlier findings on myo‐inositol in AD, which consistently revealed strong positive correlations with measures of cognitive decline and disease progression 14, 61, 62, 63. Higher levels of mI are considered a marker of neuroinflammation or “reactive astrogliosis,” and the activation of mI‐rich astrocytes and microglia is proposed as an explanation for these findings 64, 65…”

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Subsequent misfolding exposes hydrophobic residues that can then coalesce with hydrophobic ‘extrusions’ from other proteins. Some PTMs, in particular oxidations, may arise from elevated ROS levels typical of AD neuroinflammation (Liu et al ., 2011; Heneka et al ., 2015). It is revealing that AD does not affect total aggregates in the same way, implying that the underlying molecular dysfunction does not generalize to types of aggregates that accompany normal aging .…”

“…Intriguing clues have come from genetic mutations that cause such diseases to recur sporadically in pedigrees, even though familial cases typically comprise only a small fraction of the total (Lio et al ., 2003; Cardenas et al ., 2012; Abdel‐Salam, 2014; Barmada, 2015; Heneka et al ., 2015). Those mutations may render a single ‘seed’ protein susceptible to aggregation in whichever brain regions it is chiefly expressed.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Data from microbiome studies (see below) have also provided supporting evidence on this issue. Trials in nonsteroidal anti‐inflammatory drugs on AD have shown inconsistent results with most ending in failure; however, it is speculated that this may be due to timing and choice of specific anti‐inflammatory drugs (Heneka et al, 2015; St‐Amour, Cicchetti, & Calon, 2016). …”