TY  - JOUR
AB  - A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.
AU  - Hembach, S.
AU  - Schmidt, S.
AU  - Orschmann, T.
AU  - Burtscher, I.
AU  - Lickert, H.
AU  - Giesert, F.
AU  - Weisenhorn, D.M.
AU  - Wurst, W.
C1  - 70296
C2  - 55493
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation.
JO  - Neurobiol. Dis.
VL  - 194
PB  - Academic Press Inc Elsevier Science
PY  - 2024
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - BACKGROUND: Dravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course. METHODS: A knock-in mouse model of Dravet syndrome with Scn1a haploinsufficiency was used for whole proteome, seizure and behavioral analysis. Hippocampal tissue was dissected from two- (prior to epilepsy manifestation) and four- (following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantification. Proteomic data sets were subjected to bioinformatic analysis including pathway enrichment analysis. The differential expression of selected proteins was confirmed by immunohistochemical staining. RESULTS: The findings confirmed an increased susceptibility to hyperthermia-associated seizures, the development of spontaneous seizures, and behavioral alterations in the novel Scn1a-A1873V mouse model of Dravet syndrome. As expected, proteomic analysis demonstrated more pronounced alterations following epilepsy manifestation. In particular, proteins involved in neurotransmitter dynamics, receptor and ion channel function, synaptic plasticity, astrogliosis, neoangiogenesis, and nitric oxide signaling showed a pronounced regulation in Dravet mice. Pathway enrichment analysis identified several significantly regulated pathways at the later time point, with pathways linked to synaptic transmission and glutamatergic signaling dominating the list. CONCLUSION: In conclusion, the whole proteome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Some of these alterations may have an impact on excitability or may serve a compensatory function, which, however, needs to be further confirmed by future investigations. The proteomic data indicate that, due to the molecular consequences of the genetic deficiency, the pathophysiological mechanisms may become more complex during the course of the disease. As a result, the management of Dravet syndrome may need to consider further molecular and cellular alterations. Ensuing functional follow-up studies, this data set may provide valuable guidance for the future development of novel therapeutic approaches.
AU  - Miljanovic, N.*
AU  - Hauck, S.M.
AU  - van Dijk, R.M.*
AU  - Di Liberto, V.*
AU  - Rezaei, A.*
AU  - Potschka, H.*
C1  - 62322
C2  - 50772
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model.
JO  - Neurobiol. Dis.
VL  - 157
PB  - Academic Press Inc Elsevier Science
PY  - 2021
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - The vulnerability of the mammalian brain is mainly due to its limited ability to generate new neurons once fully matured. Direct conversion of non-neuronal cells to neurons opens up a new avenue for therapeutic intervention and has made great strides also for in vivo applications in the injured brain. These great achievements raise the issue of adequate identity and chromatin hallmarks of the induced neurons. This may be particularly important, as aberrant epigenetic settings may reveal their adverse effects only in certain brain activity states. Therefore, we review here the knowledge about epigenetic memory and partially resetting of chromatin hallmarks from other reprogramming fields, before moving to the knowledge in direct neuronal reprogramming, which is still limited. Most importantly, novel tools are available now to manipulate specific epigenetic marks at specific sites of the genome. Applying these will eventually allow erasing aberrant epigenetic memory and paving the way towards new therapeutic approaches for brain repair.
AU  - Stricker, S.H.
AU  - Götz, M.
C1  - 60681
C2  - 49431
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Epigenetic regulation of neural lineage elaboration: Implications for therapeutic reprogramming.
JO  - Neurobiol. Dis.
VL  - 148
PB  - Academic Press Inc Elsevier Science
PY  - 2021
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - In addition to tissues such as liver, the plasma membrane sodium-dependent citrate transporter, NaCT (SLC13A5), is highly expressed in brain neurons, but its function is not understood. Loss-of-function mutations in the human SLC13A5 gene have been associated with severe neonatal encephalopathy and pharmacoresistant seizures. The molecular mechanisms of these neurological alterations are not clear. We performed a detailed examination of a Slc13a5 deletion mouse model including video-EEG monitoring, behavioral tests, and electrophysiologic, proteomic, and metabolomic analyses of brain and cerebrospinal fluid. The experiments revealed an increased propensity for epileptic seizures, proepileptogenic neuronal excitability changes in the hippocampus, and significant citrate alterations in the CSF and brain tissue of Slc13a5 deficient mice, which may underlie the neurological abnormalities. These data demonstrate that SLC13A5 is involved in brain citrate regulation and suggest that abnormalities in this regulation can induce seizures. The present study is the first to (i) establish the Slc13a5-knockout mouse model as a helpful tool to study the neuronal functions of NaCT and characterize the molecular mechanisms by which functional deficiency of this citrate transporter causes epilepsy and impairs neuronal function; (ii) evaluate all hypotheses that have previously been suggested on theoretical grounds to explain the neurological phenotype of SLC13A5 mutations; and (iii) indicate that alterations in brain citrate levels result in neuronal network excitability and increased seizure propensity.
AU  - Henke, C.
AU  - Töllner, K.*
AU  - van Dijk, R.M.*
AU  - Miljanovic, N.*
AU  - Cordes, T.*
AU  - Twele, F.*
AU  - Bröer, S.*
AU  - Ziesak, V.*
AU  - Rohde, M.*
AU  - Hauck, S.M.
AU  - Vogel, C.*
AU  - Welzel, L.*
AU  - Schumann, T.
AU  - Willmes, D.M.
AU  - Kurzbach, A.
AU  - El-Agroudy, N.N.
AU  - Bornstein, S.R.*
AU  - Schneider, S.A.*
AU  - Jordan, J.*
AU  - Potschka, H.*
AU  - Metallo, C.M.*
AU  - Köhling, R.*
AU  - Birkenfeld, A.L.
AU  - Löscher, W.*
C1  - 59755
C2  - 49036
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus.
JO  - Neurobiol. Dis.
VL  - 143
PB  - Academic Press Inc Elsevier Science
PY  - 2020
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p =.0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.
AU  - Maass, F.*
AU  - Michalke, B.
AU  - Willkommen, D.
AU  - Leha, A.*
AU  - Schulte, C.*
AU  - Tönges, L.*
AU  - Mollenhauer, B.*
AU  - Trenkwalder, C.*
AU  - Rückamp, D.*
AU  - Börger, M.*
AU  - Zerr, I.*
AU  - Bähr, M.*
C1  - 57385
C2  - 47783
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease.
JO  - Neurobiol. Dis.
VL  - 134
PB  - Academic Press Inc Elsevier Science
PY  - 2020
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca2+ mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPAl-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPAl-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.
AU  - Griggs, R.B.*
AU  - Santos, D.F.*
AU  - Laird, D.E.*
AU  - Doolen, S.*
AU  - Donahue, R.R.*
AU  - Wessel, C.R.*
AU  - Fu, W.*
AU  - Sinha, G.P.*
AU  - Wang, P.*
AU  - Zhou, J.*
AU  - Brings, S.*
AU  - Fleming, T.*
AU  - Nawroth, P.P.
AU  - Susuki, K.*
AU  - Taylor, B.K.*
C1  - 55578
C2  - 46422
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 76-86
TI  - Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes.
JO  - Neurobiol. Dis.
VL  - 127
PB  - Academic Press Inc Elsevier Science
PY  - 2019
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - Information about epileptogenesis-associated changes in protein expression patterns is of particular interest for future selection of target and biomarker candidates. Bioinformatic analysis of proteomic data sets can increase our knowledge about molecular alterations characterizing the different phases of epilepsy development following an initial epileptogenic insult. Here, we report findings from a focused analysis of proteomic data obtained for the hippocampus and parahippocampal cortex samples collected during the early post-insult phase, latency phase, and chronic phase of a rat model of epileptogenesis. The study focused on proteins functionally associated with cell stress, cell death, extracellular matrix (ECM) remodeling, cell-ECM interaction, cell-cell interaction, angiogenesis, and blood-brain barrier function. The analysis revealed prominent pathway enrichment providing information about the complex expression alterations of the respective protein groups. In the hippocampus, the number of differentially expressed proteins declined over time during the course of epileptogenesis. In contrast, a peak in the regulation of proteins linked with cell stress and death as well as ECM and cell-cell interaction became evident at later phases during epileptogenesis in the parahippocampal cortex. The data sets provide valuable information about the time course of protein expression patterns during epileptogenesis for a series of proteins. Moreover, the findings provide comprehensive novel information about expression alterations of proteins that have not been discussed yet in the context of epileptogenesis. These for instance include different members of the lamin protein family as well as the fermitin family member 2 (FERMT2). Induction of FERMT2 and other selected proteins, CD18 (ITGB2), CD44 and Nucleolin were confirmed by immunohistochemistry. Taken together, focused bioinformatic analysis of the proteomic data sets completes our knowledge about molecular alterations linked with cell death and cellular plasticity during epileptogenesis. The analysis provided can guide future selection of target and biomarker candidates.
AU  - Keck, M.*
AU  - van Dijk, R.M.*
AU  - Deeg, C.A.*
AU  - Kistler, K.*
AU  - Walker, A.*
AU  - von Rüden, E.L.*
AU  - Russmann, V.*
AU  - Hauck, S.M.
AU  - Potschka, H.*
C1  - 52905
C2  - 44460
CY  - San Diego
SP  - 119-135
TI  - Proteomic profiling of epileptogenesis in a rat model: Focus on cell stress, extracellular matrix and angiogenesis.
JO  - Neurobiol. Dis.
VL  - 112
PB  - Academic Press Inc Elsevier Science
PY  - 2018
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 (LRRK2)-gene, which is mutated in certain familial forms of Parkinson's disease (PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age. However, at old age the homozygous LRRK2 R1441C animals exhibit clear phenotypes related to the prodromal phase of PD such as impairments in fine motor tasks, gait, and olfaction. These phenotypes are only marginally observable in the LRRK2 knockdown animals, possibly due to activation of compensatory mechanisms as suggested by in vitro studies of synaptic transmission. Thus, at the organismal level the LRRK2 R1441C mutation does not emerge as a loss of function of the protein, but induces mutation specific deficits. Furthermore, judged by the phenotypes presented, the LRRK2-R1441C knock-in line is a valid preclinical model for the prodromal phase of PD.
AU  - Giesert, F.
AU  - Glasl, L.
AU  - Zimprich, A.
AU  - Ernst, L.
AU  - Piccoli, G.*
AU  - Stautner, C.
AU  - Zerle, J.
AU  - Hölter, S.M.
AU  - Vogt Weisenhorn, D.M.
AU  - Wurst, W.
C1  - 51238
C2  - 43100
CY  - San Diego
SP  - 179-193
TI  - The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse.
JO  - Neurobiol. Dis.
VL  - 105
PB  - Academic Press Inc Elsevier Science
PY  - 2017
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - Despite intense research efforts, the knowledge about the mechanisms of epileptogenesis and epilepsy is still considered incomplete and limited. However, an in-depth understanding of molecular pathophysiological processes is crucial for the rational selection of innovative biomarkers and target candidates. Here, we subjected proteomic data from different phases of a chronic rat epileptogenesis model to a comprehensive systems level analysis. Weighted Gene Co-expression Network analysis identified several modules of interconnected protein groups reflecting distinct molecular aspects of epileptogenesis in the hippocampus and the parahippocampal cortex. Characterization of these modules did not only further validate the data but also revealed regulation of molecular processes not described previously in the context of epilepsy development. The data sets also provide valuable information about temporal patterns, which should be taken into account for development of preventive strategies in particular when it comes to multi-targeting network pharmacology approaches. In addition, principal component analysis suggests candidate biomarkers, which might inform the design of novel molecular imaging approaches aiming to predict epileptogenesis during different phases or confirm epilepsy manifestation. Further studies are necessary to distinguish between molecular alterations, which correlate with epileptogenesis versus those reflecting a mere consequence of the status epilepticus.
AU  - Keck, M.E.*
AU  - Androsova, G.*
AU  - Gualtieri, F.*
AU  - Walker, A.*
AU  - von Rüden, E.L.*
AU  - Russmann, V.*
AU  - Deeg, C.A.*
AU  - Hauck, S.M.
AU  - Krause, R.*
AU  - Potschka, H.*
C1  - 51237
C2  - 43108
CY  - San Diego
SP  - 164-178
TI  - A systems level analysis of epileptogenesis-associated proteome alterations.
JO  - Neurobiol. Dis.
VL  - 105
PB  - Academic Press Inc Elsevier Science
PY  - 2017
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches.
AU  - Meiser, J.*
AU  - Delcambre, S.*
AU  - Wegner, A.*
AU  - Jager, C.*
AU  - Ghelfi, J.*
AU  - D'Herouel, A.F.*
AU  - Dong, X.*
AU  - Weindl, D.*
AU  - Stautner, C.
AU  - Nonnenmacher, Y.*
AU  - Michelucci, A.*
AU  - Popp, O.*
AU  - Giesert, F.
AU  - Schildknecht, S.*
AU  - Krämer, L.*
AU  - Schneider, J.G.*
AU  - Woitalla, D.*
AU  - Wurst, W.
AU  - Skupin, A.*
AU  - Weisenhorn, D.M.
AU  - Kruger, R.*
AU  - Leist, M.*
AU  - Hiller, K.*
C1  - 47804
C2  - 39503
CY  - San Diego
SP  - 112-125
TI  - Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism.
JO  - Neurobiol. Dis.
VL  - 89
PB  - Academic Press Inc Elsevier Science
PY  - 2016
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - The protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygote for the homeodomain transcription factor Engrailed 1 (En1(+/-) mice). Neurotoxin-based animal models of PD, in contrast, are characterized by the fast and partly reversible degeneration of the SNc and VTA DA neurons. The secreted protein WNT1 was previously shown to be strongly induced in the neurotoxin-injured adult ventral midbrain (VM), and to protect the SNc and VTA DA neurons from cell death in this context. We demonstrate here that the sustained and ectopic expression of Wnt1 in the SNc and VTA DA neurons of En1(+/Wnt1) mice also protected these genetically affected En1 heterozygote (En1(+/-)) neurons from their premature degeneration in the adult mouse VM. We identified a developmental gene cascade that is up-regulated in the adult En1(+/Wnt1) VM, including the direct WNT1/β-catenin signaling targets Lef1, Lmx1a, Fgf20 and Dkk3, as well as the indirect targets Pitx3 (activated by LMX1A) and Bdnf (activated by PITX3). We also show that the secreted neurotrophin BDNF and the secreted WNT modulator DKK3, but not the secreted growth factor FGF20, increased the survival of En1 mutant dopaminergic neurons in vitro. The WNT1-mediated signaling pathway and its downstream targets BDNF and DKK3 might thus provide a useful means to treat certain genetic and environmental (neurotoxic) forms of human PD.
AU  - Zhang, J.
AU  - Götz, S.
AU  - Vogt Weisenhorn, D.M.
AU  - Simeone, A.*
AU  - Wurst, W.
AU  - Prakash, N.
C1  - 45117
C2  - 37210
SP  - 32-45
TI  - A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1+/- mice.
JO  - Neurobiol. Dis.
VL  - 82
PY  - 2015
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - Proteolytic cleavage of the amyloid precursor protein (APP) by the two proteases α- and β-secretases controls the generation of the amyloid β peptide (Aβ), a key player in Alzheimer's disease pathogenesis. The α-secretase ADAM10 and the β-secretase BACE1 have opposite effects on Aβ generation and are assumed to compete for APP as a substrate, such that their cleavages are inversely coupled. This concept was mainly demonstrated in studies using activation or overexpression of α- and β-secretases. Here, we report that this inverse coupling is not seen to the same extent upon inhibition of the endogenous proteases. Genetic and pharmacological inhibition of ADAM10 and BACE1 revealed that the endogenous, constitutive α-secretase cleavage of APP is largely uncoupled from β-secretase cleavage and Aβ generation in neuroglioma H4 cells and in neuronally differentiated SH-SY5Y cells. In contrast, inverse coupling was observed in primary cortical neurons. However, this coupling was not bidirectional. Inhibition of BACE1 increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons. Our analysis shows that the inverse coupling of the endogenous α- and β-secretase cleavages depends on the cellular model and suggests that a reduction of ADAM10 activity is unlikely to increase the AD risk through increased β-secretase cleavage.
AU  - Colombo, A.*
AU  - Wang, H.*
AU  - Kuhn, P.H.*
AU  - Page, R.*
AU  - Kremmer, E.
AU  - Dempsey, P.J.*
AU  - Crawford, H.C.*
AU  - Lichtenthaler, S.F.*
C1  - 8606
C2  - 30204
SP  - 137-147
TI  - Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines.
JO  - Neurobiol. Dis.
VL  - 49
PB  - Elsevier
PY  - 2012
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - In the epileptic brain, seizures can increase hippocampal neurogenesis, while opposingly seizure-associated brain pathology has been shown to detrimentally affect neurogenesis. The long-term impact of recurrent seizures on the number of new neurons as well as their relative contribution to the granule cell layer remains an open question. Therefore we analyzed neuron addition based on genetic fate mapping in a chronic model of epilepsy comparing non-kindled animals and kindled animals having at least one generalized seizure with and without further seizures. The number of all new granule cells added to the dentate gyrus following the onset of kindling was significantly increased (7.0-8.9 fold) in kindled groups. The hyperexcitable kindled state and a prior seizure history proved to be sufficient to cause a pronounced long-term net effect on neuron addition. An ongoing continuous occurrence of seizures did not further increase the number of new granule cells in the long-term. In contrast, a correlation was found between the cumulative duration of seizures and neuron addition following a kindled state. In addition, the overall number of seizures influenced the relative portion of new cells among all granule cells. Non-kindled animals showed 1.6% of new granule cells among all granular cells by the end of the experiment. This portion reached 5.7% in the animals which experienced either 10 or 22 seizures. A percentage of 8.4% new cells were determined in the group receiving 46 seizures which is a significant increase in comparison to the control group. In conclusion, permanent genetic fate mapping analysis demonstrated that recurrent seizures result in a lasting change in the makeup of the granule cell layer with alterations in the relative contribution of newborn neurons to the granule cell network. Interestingly, the formation of a hyperexcitable kindled network even without recent seizure activity can result in pronounced long-term alterations in the absolute number of new granule cells. However, seizure density also seems to play a critical role with more frequent seizures resulting in increased fractions of new neurons.
AU  - Jafari, M.*
AU  - Soerensen, J.*
AU  - Bogdanović, R.M.*
AU  - Dimou, L.
AU  - Götz, M.
AU  - Potschka, H.
C1  - 10698
C2  - 30354
SP  - 454-463
TI  - Long-term genetic fate mapping of adult generated neurons in a mouse temporal lobe epilepsy model.
JO  - Neurobiol. Dis.
VL  - 48
IS  - 3
PB  - Elsevier
PY  - 2012
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders.
AU  - Wang, X.D.*
AU  - Chen, Y.*
AU  - Wolf, M.*
AU  - Wagner, K.V.*
AU  - Liebl, C.*
AU  - Scharf, S.H.*
AU  - Harbich, D.*
AU  - Mayer, B.*
AU  - Wurst, W.
AU  - Holsboer, F.*
AU  - Deussing, J.M.*
AU  - Baram, T.Z.*
AU  - Müller, M.B.*
AU  - Schmidt, M.V.*
C1  - 6509
C2  - 28835
CY  - Oxford, UK
SP  - 300-310
TI  - Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling.
JO  - Neurobiol. Dis.
VL  - 42
IS  - 3
PB  - Blackwell
PY  - 2011
SN  - 0969-9961
ER  - 

TY  - JOUR
AB  - gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of gamma-secretase complexes with familial AD (FAD)-associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target.
AU  - Shirotani, K.*
AU  - Tomioka, M.*
AU  - Kremmer, E.
AU  - Haass, C.*
AU  - Steiner, H.*
C1  - 1981
C2  - 24794
SP  - 102-107
TI  - Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes.
JO  - Neurobiol. Dis.
VL  - 27
IS  - 1
PB  - Academic Press
PY  - 2007
SN  - 0969-9961
ER  -