Biology subjects

Sigurdsson, E. M.

Publications and source records attributed to Sigurdsson, E. M..

6 recordsLinked to original sources

bioRxiv2026

A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated -synuclein (-syn), including Parkinsons disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti--syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing -syn in a mouse model. However, whether these sdAbs can suppress -syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti--syn sdAbs to clear pathological -syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 -syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of -syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with -syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated -syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.

neuroscience↗

bioRxiv2026

Cell-Type-Selective Cortical Pathology and Functional Deficits in Synucleinopathy

Aggregates of -synuclein (-syn), a hallmark of synucleinopathies, accumulate in the cerebral cortex accompanied by the emergence of motor symptoms, which are associated with altered cortical neuronal activity. However, the mechanism by which -syn pathology drives cortical network dysfunction, and how these alterations contribute to impaired motor execution and learning, remain unknown. Here, we adopted a multi-disciplinary approach to elucidate the pathophysiological characteristics in transgenic mice that express mutant human -syn, with minimal nigrostriatal degeneration. In vivo two-photon imaging revealed distinct alteration patterns in excitatory and parvalbumin (PV)-expressing inhibitory cortical neurons accompanying fine motor deficits during learning. Cell type specific ex vivo whole-cell recording further revealed selectively altered intrinsic properties in excitatory but not PV neurons, consistent with the preferential accumulation of -syn inclusions in excitatory rather than PV neurons within the same cortical region. These results indicate cell-type selective vulnerability in motor cortex of early stage synucleinopathy, leading to disrupted excitatory/inhibitory balance and dysregulated cortical plasticity, driving early-stage motor symptoms. This study provides evidence for selective vulnerability of excitatory neurons in cortical synucleinopathy.

neuroscience↗

bioRxiv2024

Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice

Tau protein truncated at aspartate 421 (Asp421) is a characteristic feature of Alzheimers disease (AD) and other tauopathies. It is likely to have a role in their pathogenesis by promoting tau aggregation. Here, using two tauopathy mouse models, we show that a monoclonal antibody against Asp421, 5G2, led to a) a 59-74% clearance of insoluble tau protein in the brains of JNPL3 tauopathy mice following a thirteen-week treatment period, b) a 46% decrease of tau levels in brain interstitial fluid immediately following a single dose of 5G2 as examined by brain microdialysis in awake JNPL3 mice, c) improved neuronal function and d) reduced microglial activation as determined by two-photon imaging in awake PS19 tauopathy mice, where we also found tau accumulation earlier than signs of microglial activation. For mechanistic insight using culture models, 5G2 prevented toxicity of AD brain-derived pathological tau protein, cleared intracellular tau, and prevented microgliosis. We also knocked down the intracellular Fc receptor and ubiquitin E3 ligase, TRIM21, and found a reduction in cellular retention of tau antibodies, which appeared to reduce the acute efficacy (24 h) of tau antibodies but not their longer-term efficacy (5 days). Overall, these findings strongly support the feasibility of targeting Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated abnormalities of neuronal activity precede microglial activation and that antibody-mediated tau clearance via the TRIM21 pathway is mostly transient.

neuroscience↗

bioRxiv2024

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

We previously reported altered neuronal Ca2+ dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca2+ activity profile and decreasing pathological tau in these mice 1. Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models. In this study, we first performed in vivo two-photon Ca2+ imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca2+ transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca2+ transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age. A more detailed populational analysis of the pattern of Ca2+ activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca2+ profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region. Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca2+ activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies. HighlightsO_LILayer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy. C_LIO_LIAltered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running. C_LIO_LILayer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions. C_LIO_LIAcute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction. C_LI

neuroscience↗

bioRxiv2024

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of -synuclein (-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of -syn. This sdAb derivative targets both -syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces -syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of -syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of -syn, we improved clearance of -syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

neuroscience↗

bioRxiv2022

Amyloid-β targeting immunisation in aged non-human primate (Microcebus murinus)

Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimers disease (AD) -like pathology. With the objective to improve amyloid-{beta} (A{beta}) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an A{beta} derivative, K6A{beta}1-30-NH2, in old non-human primates. Thirty-two aged (4-10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone. Even though antibody titres to A{beta} were not high, pathological examination of the mouse lemur brains showed significant reduction in intracellular A{beta} without inflammatory or haemorrhagic changes. Moreover, a trend for cognitive improvement was observed in the vaccinated primates, which was probably linked to A{beta} clearance. This A{beta} derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.

neuroscience↗