Colostrinin™ alleviates amyloid-β induced toxicity in rat primary hippocampal cultures

Colostrinin™ (CLN), a complex mixture of proline-rich polypeptides derived from colostrums, can alleviate cognitive decline in early Alzheimer's disease patients. The molecular basis of the action of CLN has been studied in vitro using human neuroblastoma cell lines. The aim of the present study was to use quantitative immunocytochemistry and immunoblotting to investigate the ability of CLN to relieve amyloid-β (Aβ)-induced cytotoxicity in rat primary hippocampal neuronal cells. Our data confirm that CLN alleviates the effect of Aβ-induced cytotoxicity and causes a significant reduction in the elevated levels of the antioxidant enzyme SOD1

Type II spiral ganglion afferent neurons drive medial olivocochlear reflex suppression of the cochlear amplifier.

The dynamic adjustment of hearing sensitivity and frequency selectivity is mediated by the medial olivocochlear efferent reflex, which suppresses the gain of the 'cochlear amplifier' in each ear. Such efferent feedback is important for promoting discrimination of sounds in background noise, sound localization and protecting the cochleae from acoustic overstimulation. However, the sensory driver for the olivocochlear reflex is unknown. Here, we resolve this longstanding question using a mouse model null for the gene encoding the type III intermediate filament peripherin (Prph). Prph((-/-)) mice lacked type II spiral ganglion neuron innervation of the outer hair cells, whereas innervation of the inner hair cells by type I spiral ganglion neurons was normal. Compared with Prph((+/+)) controls, both contralateral and ipsilateral olivocochlear efferent-mediated suppression of the cochlear amplifier were absent in Prph((-/-)) mice, demonstrating that outer hair cells and their type II afferents constitute the sensory drive for the olivocochlear efferent reflex

Loss of Central Auditory Processing in a Mouse Model of Canavan Disease

<div><p>Canavan Disease (CD) is a leukodystrophy caused by homozygous null mutations in the gene encoding aspartoacylase (ASPA). ASPA-deficiency is characterized by severe psychomotor retardation, and excessive levels of the ASPA substrate N-acetylaspartate (NAA). ASPA is an oligodendrocyte marker and it is believed that CD has a central etiology. However, ASPA is also expressed by Schwann cells and ASPA-deficiency in the periphery might therefore contribute to the complex CD pathology. In this study, we assessed peripheral and central auditory function in the <i>Aspa^lacZ/lacZ</i> rodent model of CD using auditory brainstem response (ABR). Increased ABR thresholds and the virtual loss of waveform peaks 4 and 5 from <i>Aspa^lacZ/lacZ</i> mice, indicated altered central auditory processing in mutant mice compared with <i>Aspa^wt/wt</i> controls and altered central auditory processing. Analysis of ABR latencies recorded from <i>Aspa^lacZ/lacZ</i> mice revealed that the speed of nerve conduction was unchanged in the peripheral part of the auditory pathway, and impaired in the CNS. Histological analyses confirmed that ASPA was expressed in oligodendrocytes and Schwann cells of the auditory system. In keeping with our physiological results, the cellular organization of the cochlea, including the organ of Corti, was preserved and the spiral ganglion nerve fibres were normal in ASPA-deficient mice. In contrast, we detected substantial hypomyelination in the central auditory system of <i>Aspa^lacZ/lacZ</i> mice. In summary, our data suggest that the lack of ASPA in the CNS is responsible for the observed hearing deficits, while ASPA-deficiency in the cochlear nerve fibres is tolerated both morphologically and functionally.</p></div

ABR recordings reveal hypoacusis in <i>Aspa^lacZ/lacZ</i> mice at 4 months.

<p>Representative ABR waveforms from (A) <i>Aspa^wt/wt</i> and (B) <i>Aspa^lacZ/lacZ</i> mice elicited by click stimulus. Note the substantial reduction of P4 and absence of P5 in the mutant waveform. Arrows indicate ABR thresholds. (C) ABR responses of <i>Aspa^lacZ/lacZ</i> mice have higher thresholds for the click stimulus (29.0±1.0 db, n = 5) compared with <i>Aspa^wt/wt</i> controls (23.0±1.2 dB, n = 5; p = 0.027). ABR hearing threshold was not significantly different at 16 kHz (<i>Aspa^wt/wt</i> 13.0±1.2 dB; <i>Aspa^lacZ/lacZ</i> 18.0±2.5 dB; p = 0.143) or at 24 kHz (<i>Aspa^wt/wt</i> 27.0±3.4 dB; <i>Aspa^lacZ/lacZ</i> 27.0±2.0 dB; p = 0.782). (D) Analyses of peak latencies in response to click stimuli (30 dB above threshold) showed P1 were similar between <i>Aspa^lacZ/lacZ</i> mice (1.62±0.03 ms, n = 5) and <i>Aspa^wt/wt</i> controls (1.59±0.03 ms, n = 5; p = 0.633), yet with significant differences for P2 (<i>Aspa^lacZ/lacZ</i>, 2.49±0.07 ms; <i>Aspa^wt/w</i>, 2.25±0.04 ms; p<0.001) and P3 (<i>Aspa^lacZ/lacZ</i>, 3.40±0.08 ms; <i>Aspa^wt/w</i>, 3.08±0.04 ms; p<0.001). Analysis of data was precluded for P4 and P5 due to the absence of the corresponding features in ABR waveforms from <i>aspa^lacZ/lacZ</i> animals. All data were analyzed by two-way ranked ANOVA and Holm-Sidak post-hoc comparison.</p

Normal cochlear anatomy and outer hair cell function in <i>Aspa^lacZ/lacZ</i> mice.

<p>Representative transmitted light laser scanning microscopy images of midmodiolar sections of the cochleae of <i>Aspa^wt/wt</i> (A) and <i>Aspa^lacZ/lacZ</i> mice (B) revealed normal gross anatomical organization of the cochlea including preserved organ of Corti (o/C), spiral ganglia (sg), Reissner's membrane (rm), scala vestibuli (SV), scala media (SM), scala tympany (ST), cochlear nerve (cn). (C, D) Close-up of β-III tubulin-expressing spiral ganglia neurons (sgn; red) showed no abnormalities. DAPI (blue) was used to label nuclei. (E, F) High power images of the organ of Corti, with the innervation of the hair cells (neurofilament immunofluorescence, red) overlaid on the transmitted light images. Inner hair cells (ihc) are appropriately innervated by spiral ganglion neurites. DAPI (blue) was used for counterstain. ohc, outer hair cells; Dc, Deiters' cells. (G) 2f₁-f₂ DPOAEs recorded at different primary tone frequencies showed normal thresholds, implying normal OHC electromotility and cochlear amplifier response in <i>Aspa^lacZ/lacZ</i> mice compared with <i>Aspa^wt/wt</i> controls. Two-way ANOVA on ranked data and Holm-Sidak post-hoc comparison analyses showed no genotype differences for 8 kHz (<i>Aspa^lacZ/lacZ</i>, 14.0±1.9; <i>Aspa^wt/w</i>, 13.0±1.2, p = 0.658), 16 kHz (<i>Aspa^lacZ/lacZ</i>, 22.0±2.5; <i>Aspa^wt/w</i>, 22.0±2.5, p = 1.0), or 24 kHz (<i>Aspa^lacZ/lacZ</i>, 40.0±6.1; <i>Aspa^wt/w</i>, 42.0±1.2, p = 0.556). n = 5; Bars: A–B, 100 µm; C–F, 20 µm.</p

Hypomyelination of central auditory structures in ASPA-deficient mice.

<p>Luxol Fast Blue staining of brain sections from <i>Aspa^wt/wt</i> mice (A, C, E, G, I) and <i>Aspa^lacZ/lacZ</i> mice (B, D, F, H, J) reveals demyelination in the brainstem (A–H) and midbrain (I, J) of the mutant. Hypomyelination is severe in white matter of the VIII cranial nerve adjacent to the cochlear nucleus (A, B), or axon tracts of the lateral lemniscus (G, H). Differences were less evident in inherently myelin-poor grey matter of the cochlear nucleus (C, D), superior olivary complex (E, F), and inferior colliculus (I, J). Note that Luxol Fast Blue-treated sections were counterstained with Cresyl Violet. VIII cranial nerve, VIII; cochlear nucleus, CN; superior olivary complex, SOC; lateral lemniscus, LL; inferior colliculus, CIC. Bars: 20 µm.</p

Central histopathology of <i>Aspa^lacZ/lacZ</i> mice.

<p>(A–L) Representative overviews of coronal sections from <i>Aspa^wt/w</i> mice and <i>Aspa^lacZ/lacZ</i> mice, stained with H&E (purple) and Luxol Fast Blue (blue) to visualize gross tissue integrity and myelination, respectively. Sections from forebrain (A–D), midbrain (E–H), and hindbrain (I–L) regions illustrate that vacuolization in <i>Aspa^lacZ/lacZ</i> mice is moderate in the neocortex but prominent in posterior regions including the hippocampus, thalamus, cerebellar white matter, and dorsal brainstem. Widespread demyelination is observed by reduced intensity of the Luxol Fast Blue signal, particularly in white matter. Boxes in (I–L) indicate the brainstem region containing the cochlear nucleus and VIII cranial nerve. (I’–L’) Higher magnification of the areas containing the cochlear nucleus (CN). Arrowheads indicate myelination deficits in the VIII cranial nerve (K’–L’). Bars: A–L, 1 mm; I’–L’, 100 µm.</p