Biology subjects

Hanseeuw, B.

Publications and source records attributed to Hanseeuw, B..

5 recordsLinked to original sources

bioRxiv2025

Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease

Plasma pTau217, an emerging Alzheimers disease (AD) biomarker, may reflect a synaptic response to {beta}-amyloid (A{beta}) plaques before cortical tangle formation, but its broader biological correlates remain unclear. We sought to identify associations between whole blood gene expression and plasma pTau217, and to determine whether APOE{varepsilon}4, sex, and neocortical A{beta}-PET modify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimers and accompanying LEARN studies (A4/LEARN, Agemean(SD)=72.2(4.6); 63%female). Of 20,621 genes tested (1,048 X-linked), none were directly associated with pTau217; one gene was moderated by APOE{varepsilon}4, 1,540 genes by A{beta}-PET, and 772 genes by both A{beta}-PET and sex. Over 100 of these significant associations were X-linked, supporting a role of the X chromosome in AD. Sex interactions were only observed in the presence of elevated A{beta}-PET. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated A{beta}-PET.

neuroscience↗

bioRxiv2025

Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4

INTRODUCTIONIn neurodegenerative dementias, the co-occurrence and interaction of A{beta}, tau, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODSWe analyzed 480 post-mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among A{beta}, tau, LATE-NC, -synuclein, other age-related lesions, and APOE {varepsilon}4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTSA{beta}, tau, LATE-NC, and amygdala-predominant -synuclein pathology were highly interconnected. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and -synuclein, while APOE {varepsilon}4 was mainly associated with extracellular and capillary A{beta}. DISCUSSIONAlthough Alzheimers pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.

neuroscience↗

bioRxiv2025

The Olfactory Epithelium: A Critical Gateway for Pathological Tau Propagation and a Target for Mitigating Tauopathy in the Central Nervous System

Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimers disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g. EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OEs middle stratum and in the OBs olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human post-mortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to ageing or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

neuroscience↗

bioRxiv2024

Erroneous compensation for long-latency feedback delays as origin of Essential Tremor

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with ET patients (N=24) and neurologically intact (NI) volunteers (N=28) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude, and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients early muscular responses (Short and Long-Latency Responses, 20-50 ms and 50-100 ms respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor. Significance StatementEssential Tremor origin remains poorly understood. In the present study, we focused on motor impairments associated with feedback control. Following a mechanical perturbation applied to their arm, patients short and initial long-latency stretch responses were preserved. However, we observed clear impairments during the stabilization phase that scaled with the perturbation magnitude. These results were reproduced in a computational model where delay compensation was inaccurate, suggesting that the origin of the tremor may lie in an underestimation of the delays impacting the internal monitoring of the motor commands. Conflict of interestThe authors declare no competing financial interests.

neuroscience↗

bioRxiv2020

Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

BackgroundThe {beta}-amyloid peptide (A{beta}) plays a key role in Alzheimers disease. After its production by catabolism of the amyloid precursor protein (APP) through the action of presenilin 1 (PS1)- or presenilin 2 (PS2)-dependent {gamma}-secretases, monomeric A{beta} can assemble in oligomers. In a pathological context, this eventually leads to the formation of fibrils, which deposit in senile plaques. Many studies suggest that A{beta} toxicity is related to its soluble oligomeric intermediates. Among these, our interest focuses on hexameric A{beta}, which acts as a nucleus for A{beta} self-assembly. MethodsBiochemical analyses were used to identify hexameric A{beta} in a wide range of models; cell lines, cerebrospinal fluid from cognitively impaired patients and transgenic mice exhibiting human A{beta} pathology (5xFAD). We isolated this assembly and assessed both its effect on primary neuron viability in vitro, and its contribution to amyloid deposition in vivo following intracerebral injection. In both cases, we used wild-type mice (C57BL/6) to mimic an environment where hexameric A{beta} is present alone and 5xFAD mice to incubate hexameric A{beta} in a context where human A{beta} species are pre-existing. Using CRISPR-Cas9, we produced stable knockdown human cell lines for either PS1 or PS2 to elucidate their contribution to the formation of hexameric A{beta}. ResultsIn WT mice, we found that neither in vitro or in vivo exposure to hexameric A{beta} was sufficient to induce cytotoxic effects or amyloid deposition. In 5xFAD mice, we observed a significant increase in neuronal death in vitro following exposure to 5M hexameric A{beta}, as well as a 1.47-fold aggravation of amyloid deposition in vivo. At the cellular level, we found hexameric A{beta} in extracellular vesicles and observed a strong decrease in its excretion when PS2 was knocked down by 60%. ConclusionsOur results indicate the absence of cytotoxic effects of cell-derived hexameric A{beta} by itself, but its capacity to aggravate amyloid deposition by seeding other A{beta} species. We propose an important role for PS2 in the formation of this particular assembly in vesicular entities, in line with previous reports linking the restricted location of PS2 in acidic compartments to the production of more aggregation-prone A{beta}.

neuroscience↗