Glutaminyl Cyclase in Human Cortex: Correlation with (pGlu)-Amyloid-β Load and Cognitive Decline in Alzheimer's Disease

Abstract

Brains of Alzheimer's disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Aβ was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Aβ and pGlu-Aβ concentrations were quantified by ELISA. Data on QC expression and Aβ peptide concentrations were correlated with each other and with the Mini-Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Aβ deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Aβ aggregates, but not of unmodified Aβ peptides. Elevated pGlu-Aβ load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Aβ. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Aβ formation.

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…Moreover, in AD patients a better correlation seems to exist between decline in Mini-Mental State Examination and elevated pE3-Ab, rather than load of deposits of unmodified Ab (Morawski et al, 2014). In contrast to humans, in many transgenic animal models pE3-Ab deposition often occurs later than general Ab deposition with the age of onset varying in different mouse models (Frost et al, 2013).…”

Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: A practical human model to study Alzheimer's disease vasculopathy

“…After washing, arterioles were exposed for 1-hour to 2 μM Aβ1-42 (Anaspec, Fremont CA, Sigma-Aldrich, St. Louis MO or GenScript, Piscataway NJ) ± polyethylene glycol superoxide dismutase (PEGSOD, 250 U/mL, Sigma-Aldrich) or 0.2 μM Aβ. The dose of 2 μM was chosen because it is less than but close to the published concentration of Aβ42 in cortical tissue found in autopsies of patients with Alzheimer's disease (~30,000 ng/g tissue) from the BSHRI Brain and Body Donation program (Morawski et al, 2014) and it is close to the concentrations used in published preclinical studies that showed impaired vasomotor response (Dietrich et al, 2010; Thomas et al, 1997). In living adipose arterioles treated with Aβ 2 μM, Aβ was administered intraluminally in 6 arterioles and extraluminally in 9 arterioles.…”

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

“…The predominance of pE-A␤ in the central core of plaques suggests an early involvement in amyloid deposition in the AD brain (52), whereas correlation between pE-A␤ and a decline in Mini Mental State Examination scores implicate pE-A␤ cytotoxicity in AD neurodegeneration (53,54). In parallel, markers of oxidative stress are among the earliest detectable pathological changes in transgenic AD mouse models (55) and the human AD brain (36,56,57), with numerous lines of evidence implicating A␤ as a central contributor to oxidative stress in AD (58,59).…”