Scuderi, G. | Search bioRxiv

bioRxiv2026

Finite afterload during asymmetrically cycled preload promotes fetal ventricular growth, maturation, and contractile function while suppressing fibrotic remodeling

Myocardial development requires precise modulation of its growth and maturation by the mechanical loads within cardiac cycle, including preload and afterload. However, the mechanisms by which these natural cardiac loads interact to simultaneously govern growth and maturation of the developing myocardium in both cellular and mesoscale levels remain poorly understood. Here, we developed a naturally engineered fetal ventricular tissue (NFVT) platform that enables the application of afterload under dynamic preload using cyclic stretching with an asymmetrical duty cycle (asymmetrically cycled preload) to better replicate the natural cardiac loading in chick NFVT. Our results showed that low afterload (LA) enhanced NFVT contractile function with sustained tissue growth and improved cardiomyocyte maturation while suppressing fibrosis phenotypes. These effects were associated with reduced YAP1 and NOTCH activation in cardiomyocytes and enhanced tissue architecture. In contrast, high afterload (HA) induced contractile impairment with fibrotic remodeling through activation of cardiomyocyte PIEZO1/YAP1 signaling and sustained fibroblast entanglement. TeaserLow afterload under asymmetrically cycled preload promotes NFVTs contractile function with sustained tissue growth and cardiomyocyte maturation while suppressing fibrosis phenotypes through regulation of cellular mechanotransduction, including minimal PIEZO1 expression and inhibited YAP1 and NOTCH activation in cardiomyocytes, and improvement of collective cellular organization.

Cell Biology↗

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↗