TY - JOUR A1 - Sendtner, Michael A1 - Arakawa, Yoshihiro A1 - Stöckli, Kurt A. A1 - Kreutzberg, Georg W. A1 - Thoenen, Hans T1 - Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival N2 - We have demonstrated that the extensive degeneration of motoneurons in the rat facial nucleus after transection of the facial nerve in newborn rats can be prevented by local ciliary neurotrophic factor (CNTF) administration. CNTF differs distinctly from known neurotrophic molecules such as NGF, BDNF and NT-3 in both its molecular characteristics (CNTF is a cytosolic rather than a secretory molecule) and its broad spectrum of biological activities. CNTF is expressed selectively by Schwann cells and astrocytes of the peripheral and central nervous system, respectively, but not by target tissues of the great variety of CNTF -responsive neurons. CNTF mRNA is not detectable by Northern blot or PCR analysis during embryonic development and immediately after birth. However, during the second post-natal week, a more than 30-fold increase in CNTF mRNA and pro tein occurs in the sciatic nerve. Since the period of low CNTF levels in peripheral nerves coincides with that of high vulnerability of motoneurons (i.e. axonallesion results in degeneration of motoneuron cell bodies), insufficient availability of CNTF may be the reason for the rate of lesioninduced cell death of early post-natal motoneurons. Highly enriched embryonic chick motoneurons in culture are supported at survival rates higher than 60% by CNTF, even in single cell cultures, indicating that CNTF acts directly on motoneurons. In contrast to CNTF, the members of the neurotrophin gene family (NGF, BDNF and NT-3) do not support the survival of motoneurons in culture. However, aFGF and bFGF show distinct survival activities which are additive to those of CNTF, resulting in the survival of virtually all motoneurons cultured in the presence of CNTF and bFGF. KW - motoneurons KW - ciliary neurotrophic factor KW - CNTF KW - nerve lesion KW - rat KW - chick KW - neurotrophic factor Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-33048 ER - TY - JOUR A1 - Kim, Jae Ho A1 - Franck, Julien A1 - Kang, Taewook A1 - Heinsen, Helmut A1 - Ravid, Rivka A1 - Ferrer, Isidro A1 - Cheon, Mi Hee A1 - Lee, Joo-Yong A1 - Yoo, Jong Shin A1 - Steinbusch, Harry W. A1 - Salzet, Michel A1 - Fournier, Isabelle A1 - Park, Young Mok T1 - Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer's disease JF - Scientific Reports N2 - Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post-mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross-validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis. KW - imaging mass spectrometry KW - neuron navigator 3 KW - dentate gyrus KW - growth factor KW - mouse model KW - neurotrophic factor KW - entorhinal cortex KW - factor expression KW - oxidative stress KW - memory deficits Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151727 VL - 5 IS - 11138 ER - TY - JOUR A1 - Förster, Carola Y. A1 - Shityakov, Sergey A1 - Scheper, Verena A1 - Lenarz, Thomas T1 - Linking cerebrovascular dysfunction to age-related hearing loss and Alzheimer’s disease — are systemic approaches for diagnosis and therapy required? JF - Biomolecules N2 - Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood–brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood–labyrinth barrier as it does to the blood–brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future. KW - Alzheimer’s disease KW - age-related hearing loss KW - neurovasculature KW - blood–brain barrier KW - blood–labyrinth barrier KW - spiral ganglion neuron KW - pharmacotherapy KW - neurotrophic factor KW - inner ear Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297552 SN - 2218-273X VL - 12 IS - 11 ER - TY - JOUR A1 - Ammar, Mohamed Raafet A1 - Thahouly, Tamou A1 - Hanauer, André A1 - Stegner, David A1 - Nieswandt, Bernhard A1 - Vitale, Nicolas T1 - PLD1 participates in BDNF-induced signalling in cortical neurons JF - Scientific Reports N2 - The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1\(^{-/-}\) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. KW - phospholipase D KW - ERK map kinease KW - long-term potentation KW - brain KW - protein RSK2 KW - dendritic growth KW - neurite outgrowth KW - neurotrophic factor KW - coffin-lowry-syndrome KW - phosphatidic acid Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139962 VL - 5 IS - 14778 ER -