QPS (Austria)

IntroductionAutism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology.MethodsThe GABAB receptor agonist R-Baclofen and the selective agonist for the 5HT7 serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR T+ Itpr3tf/J and B6.129P2-Fmr1tm1Cgr/J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests.ResultsBTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice’s ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice.ConclusionOur results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy.

Abstract BackgroundAlzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

Neurofilament-light chain (NF-L) is a well-known clinical biomarker of many neurodegenerative diseases. By analyzing amyotrophic lateral sclerosis (ALS) patients cerebrospinal fluid (CSF) or plasma, progression of NF-L levels can forecast conversion from the presymptomatic to symptomatic stage and time of survival. The use of plasma for NF-L measurement makes this biomarker exceptionally valuable for clinical studies since sample collection can be performed repeatedly without causing much harm. Detailed analyses of NF-L expression in neurodegenerative disease patient’s samples were already performed, while NF-L levels of preclinical models of ALS, Alzheimer’s and Parkinson’s disease as well as lysosomal storage diseases are still widely unknown. We therefore evaluated NF-L levels in the plasma of the ALS models SOD1-G93A low expressor and TAR6/6 mice, the Alzheimer’s disease (AD) model 5xFAD, the Parkinson’s disease model Line 61 and the Gaucher disease (GD) model 4L/PS-NA and the CSF of selected models. Our results show that NF-L levels are highly increased in the plasma of ALS, Alzheimer’s and GD models, while in the analyzed Parkinson’s disease model NF-L plasma levels barely changed. Most analyzed models show a progressive increase of NF-L levels. NF-L measurements in the plasma of the neurodegenerative disease mouse models of ALS and AD are thus a good tool to evaluate disease progression. Compared to analyses in human tissues, our results suggest a high translation value of murine NF-L levels and their progression. Furthermore, our data indicate that NF-L might also be a good biomarker for disorders with a neuronal component like some lysosomal storage diseases.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound “D3”, an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice.

Numerous studies suggest that the majority of amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Aβ (pE-Aβ, including N3pE-Aβ40/42 and N11pE-Aβ40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with Ki values ranging between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-Aβ levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for Aβ cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.

Diffusion kurtosis imaging (DKI) by measuring non-Gaussian diffusion allows an accurate estimation of the distribution of water molecule displacement and may correctly characterize microstructural brain changes caused by neurodegeneration. The aim of this study was to evaluate the ability of DKI to detect changes induced by α-synuclein (α-syn) accumulation in α-syn over-expressing transgenic mice (TNWT-61) in both gray matter (GM) and white matter (WM) using region of interest (ROI) and tract-based spatial statistics analyses, respectively, and to explore the relationship between α-syn accumulation and DKI metrics in our regions of interest. Fourteen-month-old TNWT-61 mice and wild-type (WT) littermates underwent invivo DKI scanning using the Bruker Avance 9.4 Tesla magnetic resonance imaging system. ROI analysis in the GM regions substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus and tract-based spatial statistics analysis in WM were performed. Immunohistochemistry for α-syn was performed in TNWT-61 mice and correlated with DKI findings. We found increased kurtosis and decreased diffusivity values in GM regions such as the thalamus and sensorimotor cortex, and in WM regions such as the external and internal capsule, mamillothalamic tract, anterior commissure, cingulum, and corpus callosum in TNWT-61 mice as compared to WT mice. Furthermore, we report for the first time that α-syn accumulation is positively correlated with kurtosis and negatively correlated with diffusivity in the thalamus. The study provides evidence of an association between the amount of α-syn and the magnitude of DKI metric changes in the ROIs, with the potential of improving the clinical diagnosis of Parkinson's disease. We propose diffusion kurtosis imaging as a sensitive method for detecting human α-synuclein accumulation-induced changes in brain tissue, which may be reflective of Parkinson disease stage. Boxplots show the averaged mean kurtosis (orange) and mean diffusivity (blue) under the results of the analysis (*p<0.05) in brains of wild-type (WT) and α-synuclein over-expressing (TNWT-61) mice. This approach might represent a novel biomarker for the early diagnosis of Parkinson's disease. Read the Editorial Highlight for this article on page 1117.

We report an efficient, high-energy, diode-pumped Yb:CaF2 regenerative amplifier. Energies up to 1.02 mJ at 1045-nm and 5 kHz-repetition rate in 324 fs-long pulses have been obtained with a beam quality factor of M2 =1.1.