Biology subjects

Magnusson, K. R.

Publications and source records attributed to Magnusson, K. R..

3 recordsLinked to original sources

bioRxiv2026

Appearance of Amyloid-β Early in Life Initiates Neuronal Hyper-excitability, Mitochondrial Decay, and Loss of Dendritic Complexity in the Hippocampal CA1 Region of 5xFAD Mice

Alzheimers disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and significant plaque accumulation by 4 months of age. Ex vivo electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident. Morphological analyses further demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics supported this anatomical selectivity by identifying regionally enriched molecular signatures consistent with differential vulnerability. The CA1 region exhibited more reductions in mitochondria-related transcripts than CA3 or dentate gyrus and these reductions were specifically associated with CA1 pyramidal cell neurons. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability across hippocampal subregions. This integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention aimed at delaying or preventing downstream neurodegeneration in AD.

neuroscience↗

bioRxiv2022

Effect of Nrf2 Loss on Senescence and Cognition of Tau-Based P301S Mice

Cellular senescence may contribute to chronic inflammation involved in the progression of age-related diseases such as Alzheimers Disease (AD), and its removal prevents cognitive impairment in a model of tauopathy. Nrf2, the major transcription factor for damage response pathways and regulators of inflammation, declines with age. Our previous work showed that silencing Nrf2 gives rise to premature senescence in cells and mice. Others have shown that Nrf2 ablation can exacerbate cognitive phenotypes of some AD models. In this study we aimed to understand the relationship between Nrf2 elimination, senescence, and cognitive impairment in AD, by generating a mouse model expressing a mutant human tau transgene in an Nrf2 knockout (Nrf2KO) background. We assessed senescent cell burden and cognitive decline of P301S mice in the presence and absence of Nrf2. Lastly, we administered 4.5 month-long treatments with two senotherapeutic drugs to analyze their potential to prevent senescent cell burden and cognitive decline: the senolytic drugs Dasatinib and Quercetin (DQ) and the senomorphic drug rapamycin. Nrf2 loss accelerated the onset of hind-limb paralysis in P301S mice. At 8.5 months of age, P301S mice did not exhibit memory deficits, while P301S mice without Nrf2 were significantly impaired. However, markers of senescence were not elevated by Nrf2 ablation in any of tissues that we examined. Neither drug treatment improved cognitive performance, nor did it reduce expression of senescence markers in brains of P301S mice. Contrarily, rapamycin treatment at the doses used delayed spatial learning and led to a modest decrease in spatial memory. Taken together, our data suggests that the emergence of senescence may be causally associated with onset of cognitive decline in the P301S model, indicate that Nrf2 protects brain function in a model of AD through mechanisms that may include, but do not require the inhibition of senescence, and suggest possible limitations for DQ and rapamycin as therapies for AD.

animal behavior and cognition↗

bioRxiv2020

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

IntroductionDietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function. MethodsFish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed. ResultsNitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter {gamma}-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior. ConclusionNitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.

animal behavior and cognition↗