Biology subjects

Marney, L.

Publications and source records attributed to Marney, L..

4 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↗

bioRxiv2025

The cyclic nucleotide binding sites of Swiss-Cheese, the Drosophila orthologue of human PNPLA6, are required for its catalytic function

Mutations in Swiss-cheese (SWS) or its vertebrate ortholog PNLPA6, also called Neuropathy Target Esterase (NTE), cause progressive neuronal degeneration in Drosophila and mice and several complex syndromes in humans. These include mental retardation, spastic paraplegia, ataxia and blindness and several other symptoms. SWS and PNPLA6 are widely expressed in neurons and in several glial cell types in Drosophila and mice and both cell types require SWS/PNPLA6 function autonomously. SWS and PNPLA6 are structurally and functionally conserved because expression of human or mouse PNPLA6 can replace SWS in flies. These orthologues share several domains, including the highly conserved phospholipase domain that mediates its function in deacetylating phosphatidylcholine (PC) to lysophosphatidylcholine and glycerophosphocholine. In addition, they share three cyclic nucleotide binding sites and although about 10% of the known disease-causing mutations occur in these sites, their function is still unknown. We therefore generated mutations in these sites in SWS to address what consequences this has for the function of the protein. Mutating only one site (SWSG558E) results in a partially functional protein that rescues the sws knockdown and that decreases PC when overexpressed. However, mutating all three sites (SWS{Delta}CNB) renders SWS non-functional and results in an increase of PC when overexpressed, suggesting that cyclic nucleotide binding can regulate the phospholipase function.

neuroscience↗

bioRxiv2024

Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica

BackgroundA water extract of the Ayurvedic plant Centella asiatica (CAW) improves cognitive function in mouse models of aging and Alzheimers disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plants therapeutic benefit. MethodsMouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively. ResultsExtensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level. ConclusionsFour gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.

neuroscience↗

bioRxiv2024

Amelioration of age-related cognitive decline and anxiety in mice by Centella asiatica extract varies by sex, dose and mode of administration.

We have previously reported that a water extract (CAW) of the Ayurvedic plant Centella asiatica administered in drinking water can improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here we compared the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice. Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.2, 0.5 or 1% w/w) to provide 0, 200 mg/kg/d, 500 mg/kg/d or 1000 mg/kg/d for a total of 5 weeks. An additional group of eighteen-month-old mice were treated with CAW (10 mg/mL) in their drinking water for a total of five weeks to deliver the same exposure of CAW as the highest dietary dose (1000 mg/kg/d). CAW doses delivered were calculated based on food and water consumption measured in previous experiments. In the fourth and fifth weeks, mice underwent behavioral testing of cognition, anxiety and depression (n=12 of each sex per treatment group in each test). Aged mice of both sexes showed cognitive deficits relative to young mice while only female aged mice showed increased anxiety compared to the young female mice and no differences in depression were observed between the different ages. CAW (1000 mg/kg/d) in the drinking water improved deficits in aged mice in learning, executive function and recognition memory in both sexes and attenuated the increased measures of anxiety observed in the aged female mice. However, CAW in the diet only improved executive function in aged mice at the highest dose (1000 mg/kg/d) in both sexes and did so less robustly than when given in the water. There were no effects of CAW on depression-like behavior in aged animals regardless of whether it was administered in the diet or the water. These results suggest that CAW can ameliorate age-related changes in measures of anxiety and cognition and that the mode of administration is important for the effects of CAW on resilience to these age-related changes.

animal behavior and cognition↗