Biology subjects

Head, B. P.

Publications and source records attributed to Head, B. P..

3 recordsLinked to original sources

bioRxiv2025

Boolean Network Modeling Identifies Cognitive Resilience in the First Murine Model of Asymptomatic Alzheimer Disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder defined by amyloid beta (A{beta}) plaques and neurofibrillary tangles (NFTs), yet approximately 20-30% of aged individuals exhibit these hallmark lesions without developing cognitive impairment--a clinically silent condition termed asymptomatic AD (AsymAD). The molecular basis of this cognitive resilience remains poorly understood due to a lack of mechanistic models. Here, we integrate systems-level Boolean network modeling with in vivo validation to define the transcriptomic logic of AsymAD and uncover a novel preclinical model. Using Boolean implication networks trained on large-scale human cortical RNA-seq datasets, we identified a robust and invariant AD gene signature that accurately stratifies disease states across independent datasets. Application of this signature to Chromogranin A- deficient PS19 mice (CgA-KO/PS19) revealed a unique resilience phenotype: male mice developed AD-like molecular and neuropathological profiles in the pre-frontal cortex yet retained intact learning and memory. Female CgA-KO/PS19 mice displayed even greater protection, including reduced Tau phosphorylation and preserved synaptic ultrastructure. These findings establish the first validated murine model of AsymAD and identify CgA as a modifiable node linking neuroendocrine signaling, Tauopathy, and cognitive preservation. This work provides a scalable platform to probe sex-specific resilience, uncover early-stage biomarkers, and accelerate preventive therapeutic development in AD.

neuroscience↗

bioRxiv2024

Catestatin improves heart metabolic flexibility by promoting mitochondrial structure and function

Hypertension, a major cause of cardiomyopathy, is one of the most critical risk factors for heart failure and mortality worldwide. Loss of metabolic flexibility of cardiomyocytes is one of the major causes of heart failure. Although Catestatin (CST) treatment is known to be both hypotensive and cardioprotective, its effect on cardiac metabolism is unknown. In this study, we undertook a transcriptomic approach to identify differentially expressed genes that were filtered using Boolean implication relationships to develop a model of gene regulation in saline or CST-supplemented CST knockout (CST-KO) mice. The analysis revealed a set of gene signatures (fibroblast, cardiomyocyte, and macrophage) rescued after CST supplemented CST-KO mice compared to wild-type. Furthermore, we independently validated these gene signature models using publicly available patient datasets. Since the gene signature includes genes related to glucose, fatty acid metabolism, and mitochondrial function, we assessed the glucose and fatty acid uptake after CST treatment. We found that CST treatment can restore the cardiac metabolic inflexibility in CST-KO heart due to the metabolic shift of glucose utilization to fatty acid as energy source. Binding studies after immunoprecipitation and mass spectrometry revealed CST binding with ATP synthase, supported by molecular simulation and computational modeling that predicted CST binding to /{beta} subunit of ATP synthase. Colocalization of CST with mitochondria and increased mitochondrial membrane potential and ATP production upon CST treatment in neonatal cardiomyocytes further exhibit CST as a key regulator of cardiac metabolism and mitochondrial function.

physiology↗

bioRxiv2020

Synapsin-caveolin-1 mitigates cognitive deficits and neurodegeneration in Alzheimer's disease mice

AD presents with severe neurodegeneration which leads to cognitive deficits and dementia. Identifying the molecular signals that attenuate neurodegeneration in AD may be exploited as therapeutic targets. This study revealed that transgenic AD mice (PSAPP) exhibit decreased caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in MLRs. We thus developed an in vivo gene therapy that re-expresses neuronal-targeted Cav-1 using the synapsin promoter (SynCav1). While AD mice showed significant learning and memory deficits at 9 and 11 months, AD mice that received hippocampal SynCav1 (AD-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, AD-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis. Thus, SynCav1 demonstrates translational potential to treat AD by delaying neurodegeneration. SummaryTransgenic PSAPP mice exhibit decreased hippocampal expression of the membrane lipid raft (MLR) scaffolding protein caveolin-1. Synapsin-promoted re-expression of Cav-1 (termed SynCav1) mitigated neuropathology and cognitive deficits. SynCav1 gene therapy has the potential to treat AD and other forms of neurodegeneration.

neuroscience↗