Biology subjects

Rose, S. E.

Publications and source records attributed to Rose, S. E..

4 recordsLinked to original sources

bioRxiv2025

Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease

BACKGROUNDAlzheimers disease (AD) is associated with amyloid plaques and can be caused by autosomal dominant mutations in APP or PSEN1/2, which form an enzyme substrate complex. Decreases in catalysis of AD mutant APP and PSEN1 supports the hypothesis that membrane delimitation of KAT5 could contribute to AD. METHODSWe compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human WT and AD neurons. RESULTSThe Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons. DISCUSSIONThis analysis supports the hypothesis that KAT5 nuclear signaling down stream of APP cleavage plays a pivotal role in neuronal homeostasis and immune regulation.

neuroscience↗

bioRxiv2025

The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function

BackgroundSynaptic dysfunction is an early feature of Alzheimers disease (AD) and a significant contributor to cognitive decline and neurodegeneration. Proper localization of proteins involved in pre-and post-synaptic composition is dependent on endosomal recycling and trafficking. Alterations in trafficking complexes, such as retromer, have been shown to impair neuronal synaptic function. The SORL1 gene has been strongly implicated in AD pathogenesis and its protein product, SORLA, is an endosomal receptor that works in conjunction with retromer to regulate endosomal recycling. MethodsWe utilized our established human induced pluripotent stem cell (hiPSC) derived excitatory cortical neuron model to examine SORL1s role in synaptic protein composition and neuronal function. We used Quantitative Multiplex co-Immunoprecipitation (QMI), a mesoscale proteomics assay to measure synaptic protein interactions, immunocytochemistry to assay synapses and AMPA receptor subunits, and multi-electrode arrays (MEAs) to measure neuronal function of SORL1 KO and isogenic control hiPSC derived neurons. ResultsWe show that loss of SORL1 expression significantly changes many synaptic protein-protein interactions and patterns of expression. We demonstrate that SORL1 deficient neurons are hyperactive and that the increased activity is driven by glutamatergic neurotransmission. Hyperexcitability has been seen in other models of AD with familial AD variants in amyloid precursor protein and presenilin genes, due to the increases in amyloid beta (A{beta}) peptides. In the case of SORL1 deficiency, the hyperexcitability we observe is primarily due to mis-trafficking of synaptic proteins, rather than an overall increase in A{beta}. Finally, we find that SORL1 deficient neurons have impaired synaptic plasticity. ConclusionsThese findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis. Furthermore, our work supports further emphasis on exploring the SORL1-retromer pathway for therapeutic development in AD.

neuroscience↗

bioRxiv2016

Structural and functional brain changes following four weeks of unimanual motor training: evidence from behaviour, neural stimulation, cortical thickness and functional MRI

Although different aspects of neuroplasticity can be quantified with behavioural probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practised a sequence of finger-thumb opposition movements for 10 minutes each day with their left hand. After four weeks, performance for the practised sequence improved significantly (p < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practised, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p-FWE < 0.001) reductions in functional MRI activation for execution of the learned sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), as well as sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right ( trained) primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex and potentially the right supplementary motor area. Such findings are consistent with LTP-like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously non-utilised tissue.

neuroscience↗

bioRxiv2016

Structural and functional brain changes following four weeks of unimanual motor training: evidence from fMRI-guided diffusion MRI tractography

We have reported reliable changes in behaviour, brain structure and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 mins daily, over four weeks. Here we extend these findings by employing diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group p<0.01 FWE) and widespread microstructural changes were detected across the motor system of the trained hemisphere. Specifically, region-of-interest based analyses of diffusion MRI (n=21) revealed significantly increased fractional anisotropy in the right caudate nucleus (4.9%; p<0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (-1.3%; p<0.05 FWE). Diffusion MRI tractography (n=22), seeded by sensorimotor cortex fMRI activation, also revealed increased fractional anisotropy in the right corticomotor tract (mean 3.28%; p<0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticomotor tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; p<0.05 FWE) and right supplementary motor area (18/22 participants; p<0.05 FWE). Equivalent changes in FA were not seen in the left ( non-trained) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training.

neuroscience↗