Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation

Distortion Product Emissions in Normal-Hearing and Low-Frequency Hearing Loss Carriers of Genes for Waardenburg's Syndrome

Eight patients with Waardenburg's syndrome (WS) with normal hearing and 3 additional patients exhibiting a low-frequency hearing loss were tested for the level of the acoustic distortion product 2f1-f2 by means of the Otodynamics Distortion Product Analyser (ILO92). Wide notches in distortion product otoacoustic emissions (DPOAEs) between 1,000 and 3,000 Hz were found in 7 (12 ears, 87.5%) examined patients with normal audiograms, which was a significantly higher rate than that found in the control group (10%). The 3 patients with low-frequency hearing loss gave a consistent pattern in audiometric configuration shown by both pure tone audiograms and DPOAEs. It is concluded from these initial results that DPOAEs may be a useful approach to identifying subclinical pathologic aberrations in the inner ear in WS patients, and may be a predictor of low-frequency sensorineural hearing loss