INTRODUCTION Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy.METHODS AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.RESULTS SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.DISCUSSION These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder defined by extracellular deposition of amyloid-β (Aβ) plaques and intracellular accumulation of hyperphosphorylated Tau in neurofibrillary tangles (NFTs). Notably, approximately 20–30% of older individuals harbor substantial amyloid and Tau pathology yet remain cognitively intact, a clinically silent state referred to as asymptomatic Alzheimer’s disease (AsymAD). The biological basis of this cognitive resilience remains poorly understood, in large part due to the absence of mechanistic frameworks and preclinical models that dissociate neuropathology from cognitive decline. Here, we integrate systems-level Boolean network modeling with in vivo validation to define the transcriptomic logic of AsymAD and establish an experimentally tractable murine model of cognitive resilience. Boolean implication networks trained on large-scale human cortical RNA-sequencing datasets identified a robust, invariant AD gene signature that accurately stratified disease states across multiple independent cohorts. Reverse translation of this signature to transgenic mouse models revealed a striking dissociation between molecular pathology and behavioral outcome in Chromogranin A (CgA)–deficient PS19 mice (CgA-KO/PS19). Male CgA-KO/PS19 mice exhibited AD-like transcriptomic and neuropathological features in the prefrontal cortex while retaining intact learning and memory. Female CgA-KO/PS19 mice demonstrated even greater resilience, characterized by suppression of Tau aggregation and preservation of synaptic ultrastructure. Together, these findings establish a validated murine model of AsymAD and identify CgA as a modifiable molecular node linking neuroendocrine signaling, Tauopathy, and cognitive preservation. This integrative computational–experimental framework provides a scalable and generalizable platform for dissecting sex-specific mechanisms of cognitive resilience, identifying early biomarkers of disease trajectory, and enabling mechanism-guided development of preventive therapeutic strategies for AD.

PURPOSE:Myelin integrity is increasingly recognized as a potential factor in Alzheimer's disease (AD) pathology, making accurate quantification of myelin essential for elucidating its role in the progression of the disease. This study aims to evaluate the potential of ultrashort echo time magnetization transfer (UTE-MT) imaging for assessing myelin-related alterations in an APP knock-in mouse model of AD (hereafter referred to as APPKI mice). METHOD:Eighteen APPKI mice (∼14 months; 9 females/9 males) and fourteen age-matched wild-type C57BL/6 (WT) (8 females/6 males) were scanned on a 3T Bruker scanner. Two sets of UTE-MT data (TR=80 ms, TE=0.026 ms) were acquired with an MT pulse power of 1500° (θ=1500°) and frequency offset of 2 kHz (Δf = 2 kHz) (MTon), and with θ=500° and Δf = 50 kHz (MToff), respectively. UTE-MT ratio (UTE-MTR) maps, calculated as (MToff - MTon)/MToff, were generated for comparing APPKI and WT mice. Luxol Fast Blue (LFB) staining was employed to quantify myelin density in both the APPKI and WT groups by measuring average optical density (AOD) in the corpus callosum (CC) and hippocampus. A fear conditioning paradigm was conducted to assess cognitive function. Students' t-tests were used to compare UTE-MTR and AOD values, as well as freezing behavior between APPKI and WT groups. Furthermore, Pearson's correlation was used to quantify the association between UTE-MTR and AOD measurements. RESULTS:The UTE-MTR values showed a significant reduction in the APPKI group compared to the WT group in both the CC (0.401±0.010 vs. 0.416±0.006, p < 0.0001) and the hippocampus (0.334±0.012 vs. 0.343±0.006, p < 0.05). Histological validation via LFB staining confirmed these findings, revealing a significantly lower AOD in APPKI mice across the same regions (p < 0.05). Pearson correlation analysis demonstrated a positive association between UTE-MTR and AOD in the corpus callosum for the APPKI group (r = 0.8174, P = 0.0132), while no significant correlation was observed in the hippocampus in either group. Additionally, APPKI mice exhibited significant impairments in fear learning, contextual memory recall, and cue memory recall compared with WT controls (p < 0.05), further supporting myelin-related cognitive deficits in this model. CONCLUSION:Our findings suggest that UTE-MTR is a promising tool for detecting myelin-related changes in APPKI mice, with potential to monitor myelin alterations and cognitive deficits associated with AD pathological progression and to evaluate therapeutic efficacy in AD research.

Abstract Hypertension is a major risk factor for heart failure, characterized by impaired energy metabolism and mitochondrial dysfunction. The endogenous peptide catestatin (CST) has known cardiovascular protective effects, but its role in cardiac metabolism remains unclear. Here, we show that CST regulates cardiac metabolic pathways through integrated transcriptomic and network analyses, identifying cell-type-specific gene programs that are disrupted in its absence and restored with supplementation. Comparative analysis with human heart failure datasets reveals conserved alterations in glucose and fatty acid metabolism and mitochondrial function. Functional studies demonstrate that CST restores metabolic flexibility by shifting substrate utilization toward glucose oxidation. Mechanistically, CST enhances mitochondrial ATP production by interacting with ATP synthase and improving membrane potential and enzyme activity. These findings establish CST as a key regulator of cardiac energy metabolism and reveal an endocrine–mitochondrial signaling axis with therapeutic potential for hypertension-associated heart failure.

Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant SOD-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (ICV) route of administration (ROA), an alternative CNS delivery strategy that is less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1G93A mice. ICV administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as a preclinical proof-of-concept that ICV delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1G93A mice.

Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1G93A mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1G93A mice.

INTRODUCTION:Amyloid precursor protein (APP) undergoes striking changes following traumatic brain injury (TBI). Considering its role in the control of gene expression, we investigated whether APP regulates transcription and translation following TBI. METHODS:We assessed brain morphology (n = 4-9 mice/group), transcriptome (n = 3 mice/group), proteome (n = 3 mice/group), and behavior (n = 17-27 mice/group) of wild-type (WT) and APP knock-out (KO) mice either untreated or 10-weeks following TBI. RESULTS:After TBI, WT mice displayed transcriptional programs consistent with late stages of brain repair, hub genes were predicted to impact translation and brain proteome showed subtle changes. APP KO mice largely replicated this transcriptional repertoire, but showed no transcriptional nor translational response to TBI. DISCUSSION:The similarities between WT mice following TBI and APP KO mice suggest that developmental APP deficiency induces a condition reminiscent of late stages of brain repair, hampering the control of gene expression in response to injury. HIGHLIGHTS:10-weeks after TBI, brains exhibit transcriptional profiles consistent with late stage of brain repair. Developmental APP deficiency maintains brains perpetually in an immature state akin to late stages of brain repair. APP responds to TBI by changes in gene expression at a transcriptional and translational level. APP deficiency precludes molecular brain changes in response to TBI.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by amyloid beta ( A β ) 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.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive synaptic loss and cognitive decline. Gene therapy that augments intrinsic neuroprotective pathways offers a promising strategy to mitigate neurodegeneration and prevent further cognitive loss. Caveolin-1 (Cav-1), a membrane lipid raft (MLR) scaffolding protein, regulates multiple pro-growth and pro-survival signaling pathways within plasmalemmal microdomains. Previously, we showed that AAV9-Synapsin-promoted Cav-1 (SynCav1) delivered to presymptomatic AD mice preserved cognitive functions and MLR-associated neurotrophic signaling. However, the therapeutic potential of SynCav1 delivered at the symptomatic stage of AD had not been tested. Therefore, the current study investigated the effect of hippocampal SynCav1 delivery at symptomatic age in two distinct preclinical AD models of amyloid pathology: PSAPP and APPKI mice. Our results demonstrated that SynCav1 delivery to PSAPP and APPKI mice at symptomatic age consistently preserved hippocampal-dependent memory. Transcriptome profiling revealed that PSAPP-SynCav1 mice exhibited a similar transcript profile to age-matched wild-type mice. Gene Ontology enrichment analysis indicated downregulation of neurodegeneration-specific pathways and upregulation of synaptic and cognitive-related pathways in PSAPP-SynCav1 mice. In vitro, SynCav1-transfected mouse primary cortical neurons exhibited increased p-CaMKII and p-CREB expression, suggesting that SynCav1 may protect the CNS by enhancing neuronal and synaptic activity. Furthermore, activity-dependent neuroprotective protein (ADNP) was identified as a potential candidate mediating SynCav1’s neuroprotective effects on cognition. Subcellular membrane fractionation revealed that SynCav1 preserved MLR-localized pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), a well-known regulator of ADNP expression. Together, these findings highlight SynCav1 as a unique and promising gene therapy candidate in the treatment of AD.

Background and Purpose: Traumatic brain injury (TBI) imposes life-long physical, psychological, and financial burdens on affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarette (E-cig) on TBI-associated behavioral and biochemical changes. Experimental Approach: Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cigarette (E-Cig) vapor for six weeks. The effects of chronic nicotine exposure on sensorimotor functions, locomotion, and sociability were evaluated by nesting, open field, and social approach, respectively. Immunoblots were performed to assess changes of mature brain-derived neurotrophic factor (mBDNF) and associated downstream signaling proteins (p-Akt and p-Erk). Histological analyses of the cortex were performed to evaluate the effects of chronic nicotine exposure on Microglia-mediated neuroinflammation. Key Results: Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histology analysis revealed that chronic nicotine exposure increased the survival of cortical neurons in the perilesion cortex. Immunoblots of cortical tissue revealed that chronic nicotine exposure significantly upregulated mBDNF expression, P-Erk, and p-Akt in the perilesion cortical tissue of CCI mice. Additional IF microscopy revealed elevated mBDNF and p-Akt expression was predominantly localized in cortical neurons of CCI mice. Furthermore, immunolabeling of Iba1 showed that chronic nicotine exposure attenuates microglia-mediated chronic neuroinflammation in the perilesional cortex of CCI mice. Conclusions and Implications: Post-injury chronic nicotine exposure via vaping facilitates sensorimotor function recovery by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signaling. Results from this study support the neuroprotective properties of nicotine, further investigation is needed due to its highly addictive nature.

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 α/β 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.

AIM:Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. METHODS:We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. RESULTS:Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. CONCLUSIONS:The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

Muscle wasting occurs with aging and may be a result of oxidative stress damage and potentially inadequate protection by lipophilic antioxidants, such as vitamin E. Previous studies have shown muscular abnormalities and behavioral defects in vitamin E-deficient adult zebrafish. To test the hypothesis that there is an interaction between muscle degeneration caused by aging and oxidative damage caused by vitamin E deficiency, we evaluated long-term vitamin E deficiency in the skeletal muscle of aging zebrafish using metabolomics. Zebrafish (55 days old) were fed E+ and E− diets for 12 or 18 months. Then, skeletal muscle samples were analyzed using UPLC-MS/MS. Data were analyzed to highlight metabolite and pathway changes seen with either aging or vitamin E status or both. We found that aging altered purines, various amino acids, and DHA-containing phospholipids. Vitamin E deficiency at 18 months was associated with changes in amino acid metabolism, specifically tryptophan pathways, systemic changes in the regulation of purine metabolism, and DHA-containing phospholipids. In sum, while both aging and induced vitamin E deficiency did have some overlap in altered and potentially dysregulated metabolic pathways, each factor also presented unique alterations, which require further study with more confirmatory approaches.

The shortfin mako sharks ( Isurus oxyrinchus) belongs to the family Lamnidae, which is a group of high performance regional endothermic elasmobranch fishes that has metabolic rates (47.4±8 ml/kg/min) higher than ectothermic elasmobranchs, and also rivals that of mammals. As in all elasmobranchs, the mako sharks do not possess direct cardiac sympathetic innervation to elevate cardiac performance, but it still retains an ancient design of a capacious semi-rigid pericardium (5.4±0.6 ml/kg) likely to accommodate its large atrial diastolic volume. This study test the hypothesis that the increase in cardiac output in the mako is influenced by a strong positive lusitrophic effect that serves to increase stroke volume, which in turn invokes the Frank-Starling’s effects. The objectives is to show differences in the physiology and biochemical properties between mako (Is) and an ectothermic blue shark ( Prioance glauca, Pg), both are oceanic species and share similar life history. Echocardiography showed a higher early to late filling velocity ratio (p=0.036) in the Is (0.92±0.16, [n=15]) than in Pg (0.45±0.04, [9]). The early time velocity integral is also greater in Is (8.8±2.4 cm, [15]) vs Pg (6.8±0.8 cm [9]) indicating a stronger conduit filling imparted by the energy from previous systole in Is. However, basal cAMP (Is: 31±12 [7] vs Pg: 31±1 [3] fmol/min/μg) and stimulated cAMP with isoproterenol+GTPγS (Is: 65±21 [7] vs Pg: 59±7 [3] fmol/min/μg) activity are similar in both groups. This suggests that the differences in ventricular contractility are not through the classic adrenergic signaling pathway involving adenylyl cyclases, but likely through the mechanical stretching of the myofibrils from diastole. Caveolin distribution of the ventricular tissues following sucrose density gradient shows a higher degree of Caveolin-1/3 in the buoyant fraction and little in the in the heavy fraction in both shark species indicating an absence of t-tubules. However, Is shows a remarkably high amount of buoyant Cav-1/3 fraction compared to Pg. We posit that the high fraction abundance of Cav-1/3 provides a gateway for corticotropin-releasing factor, such as urotensin I or possibly an ancestral precursor of urocortin, which has been shown to elevate heart function in mammals. The study is supported by NSF IBN93-16621. No disclosure. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Myelin water imaging (MWI) has been proposed as a myelin-specific technique to quantify water trapped within or tightly bound to myelin bilayers and thus provides an indirect assessment of myelin content and integrity. In this study, we developed and evaluated a novel 3D short TR adiabatic inversion recovery prepared short echo time (STAIR-STE) Cones sequence for robust MWI on a clinical 3T scanner. Our results show that the 3D STAIR-STE Cones sequence robustly suppresses long-T2 intra/extracellular water signals and provides selective volumetric imaging and quantification of myelin water fraction in the whole brain.

We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of reactive astrogliosis.

Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair GLT8D1 glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading to neurotoxicity is unclear. Here we show that a p.R92C mutation causes fragmentation of the Golgi network and reduces ganglioside expression within membrane lipid rafts (MLRs), leading to impaired neurotrophin signalling. Expression of p.R92C-GLT8D1 in HEK293 cells and mouse primary neurons reduces expression of GM1 gangliosides within the cell plasma membrane leading to disruption of MLRs. Furthermore, p.R92C-GLT8D1 reduces TrkB-mediated pro-survival signalling in MLRs isolated from primary neurons. Interestingly, up-regulation of wild-type GLT8D1 enhances MLRs and promotes pro-survival signalling through TrkB. This closely mirrors findings for another ALS gene, CAV1 , suggesting convergence on a common pathogenic pathway. Other ALS genes have been associated with Golgi dysfunction and may disrupt the same pathway, suggesting a potential new therapeutic approach via upregulation of GLT8D1. Graphical Abstract