Biology subjects

Figueroa, H.

Publications and source records attributed to Figueroa, H..

3 recordsLinked to original sources

bioRxiv2023

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy

Accumulation of tau in synapses in Alzheimers disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of pathology through synaptically connected neurons. Synaptic loss correlates with a decline in cognition, providing an opportunity to investigate strategies to target synaptic tau to rescue or prevent cognitive decline. One of the promising synaptic targets is the 5-HT4 receptor present post-synaptically in the brain areas involved in the memory processes. 5-HT4R activation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tauopathy. The goal of this study was to investigate the impact of stimulation of 5-HT4R in tauopathy mice. Our results show that 5-HT4R agonism led to reduced tauopathy and synaptic tau and correlated with increased proteasome activity and improved cognitive functioning in PS19 mice. Thus, stimulation of 5-HT4R offers a promising therapy to rescue synapses from toxic synaptic tau.

neuroscience↗

bioRxiv2022

ApoE isoforms differentially regulate neuronal membrane proteasomes to shift the threshold for pathological aggregation of endogenous Tau

Neuroproteasomes are a subset of 20S proteasomes that are localized to the neuronal plasma membrane and degrade newly synthesized proteins. To date, the molecular composition of neuroproteasomes is undefined, and moreover, whether neuroproteasomes can influence protein aggregation with relevance to neurodegenerative disorders remains unexplored. Using a Cre-dependent conditional knock-in mouse line to endogenously tag the proteasome, we find that neuroproteasomes co-purify with ApoE, the most significant risk factor for late-onset Alzheimers Disease (AD). We discover that neuroproteasome membrane localization is differentially modulated by ApoE isoforms (E4<E3<E2) in vitro, in vivo, and in human postmortem samples. We synthesized selective, neuroproteasome-specific inhibitors and discovered that neuroproteasome inhibition induces aggregation of endogenous mouse and human Tau, without the need for seeding or pathogenic mutations. Using hApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Neuroproteasome inhibition in vivo is sufficient to induce sarkosyl-insoluble and Thioflavin-S positive endogenous Tau aggregates in only three days, which are completely abrogated by co-application of cycloheximide. Newly synthesized Tau levels increase threefold after neuroproteasome inhibition, leading us to posit that newly synthesized Tau is uniquely susceptible to aggregation due to neuroproteasome dysfunction. Overall, our data define neuroproteasomes as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimers Disease.

neuroscience↗

bioRxiv2020

Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy

In the early stages of Alzheimers disease (AD), tau pathology first develops in the entorhinal cortex (EC), then spreads to the hippocampus and at later stages, to the neocortex. Pathology in the neocortex correlates with impaired cognitive performance. Overall, tau pathology correlates well with neurodegeneration but the spatial and temporal association between tau pathology and overt volume loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) we mapped the spatio-temporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, co-registered in vivo MRI atlas identified particular regions in the medial temporal lobe (MTL) that had significant volume reduction. The medial entorhinal cortex (MEC) and pre-/para-subiculum (PPS) had the most significant atrophy at the early stage, but atrophy then spread into the hippocampus, most notably, the CA1, dentate gyrus (DG) and subiculum (Sub). TBM-related atrophy in the DG and Sub preceded overt cell loss that has been reported in ex vivo studies in the same mouse model. By unifying an ex vivo 3D reconstruction of tau pathology with the TBM-MRI results we mapped the progression of atrophy in the MTL with the corresponding spread of tau pathology. Our study shows that there is an association between the spread of tau pathology and TBM-related atrophy from the EC to the hippocampus, but atrophy in the DG and Sub preceded overt cell loss. One Sentence SummarySpread of tau pathology in a mouse model of Alzheimers disease assessed by MRI was associated with reduced brain tissue volume but not neuronal loss.

neuroscience↗