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bioRxiv2025

A Novel Mouse Model of Parkinson's Disease for Investigating Progressive Pathology and Neuroprotection

Developing animal models that successfully recapitulate the features of progressive Parkinsons disease (PD) is crucial for understanding disease progression mechanisms and creating effective therapeutic interventions. In this study, we created a mouse model of PD by overexpressing -synuclein through a combined injection of AAV6--synuclein and preformed fibrils (PFFs) into the medial and lateral substantia nigra (SN). We also demonstrated that chronic administration of the c-Abl inhibitor PD180970 provides neuroprotection in this model. Mice injected with the AAV6--synuclein and PFF combination showed a progressive loss of dopaminergic (DA) neurons in the SN and their projections in the striatum over 24 weeks. This neuronal loss coincided with a time-dependent accumulation of phosphorylated -synuclein (p-syn) in the SN. The p-syn aggregates spread to synaptically connected DARPP-32-positive neurons in the striatum and further extended to the cortex. We also observed a contralateral spread of p-syn aggregates. Additionally, -synuclein overexpression led to a significant increase in activated microglia and astrocytes at all timepoints, with the strongest activation occurring early and gradually diminishing over time. Daily administration of PD180970 significantly reduced the loss of DA neurons caused by -synuclein injection and decreased the accumulation of p-syn in the SN. PD180970 treatment also reduced the neuroinflammation significantly. Overall, the combined injection of AAV6--synuclein and preformed fibrils into the mouse brain establishes a robust PD model, enabling detailed mechanistic studies of the disease. We further demonstrate the models utility for chronic neuroprotection studies using the potential drug PD180970, highlighting its broad applicability. Significance StatementThis study establishes a robust mouse model of Parkinsons disease (PD) by combining AAV6-mediated -synuclein overexpression and preformed fibrils (PFFs) to replicate key features of PD, such as progressive dopaminergic neuron loss, phosphorylated -synuclein accumulation, and neuroinflammation. The model captures the spread of pathological aggregates to synaptically connected brain regions, closely mimicking the human disease. By testing the c-Abl inhibitor PD180970, we demonstrate its neuroprotective effects, including reduced neuronal loss, decreased -synuclein accumulation, and neuroinflammation highlighting its therapeutic potential. This model offers a valuable platform for investigating PD mechanisms and evaluating novel interventions, bridging the gap between preclinical and clinical applications.

neuroscience↗

bioRxiv2025

Astrocytic activation of EMMPRIN contributes to their pathological phenotype in ALS.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterised by the degeneration of upper and lower motoneurons. Onset and progression of the disease are determined by both cell-autonomous neuronal dysfunctions and non-cell-autonomous factors, mainly due to activation of glial cells such as astrocytes and microglia. The Extracellular Matrix Metalloproteinases INducer (EMMPRIN), a glycoprotein expressed by various cell types including neurons, is the major activator of matrix metalloproteinases (MMPs) synthesis and release. EMMPRIN activation can be induced by peptidyl-prolyl isomerase A (PPIA), a chaperone protein with cis/trans isomerase activity, that exhibits cytokine- and chemokine-like behaviour. Previous studies showed that PPIA is highly released in the cerebrospinal fluid (CSF) of ALS patients and animal models where, by activating EMMPRIN on motoneurons, induces neuronal death. Here, we show that EMMPRIN is expressed also by astrocytes, suggesting this cell type as sensitive as motoneurons to PPIA-mediated EMMPRIN activation. We observed that that PPIA-mediated EMMPRIN activation prompt astrocytes toward a pro-inflammatory profile. Interestingly, we found that this pathogenic profile can be reverted by an anti-EMMPRIN antibody. Finally, we provide evidence that the activation of EMMPRIN is relevant for mutant SOD1 and TDP-43 conditions. In conclusion, we demonstrate that EMMPRIN activation in ALS occurs also in astrocytes where it exacerbates their pathological phenotype possibly contributing to the progression of the disease. Furthermore, we suggest the potential use of an anti-EMMPRIN antibody to reduce astrocytic activation during the disease.

neuroscience↗

bioRxiv2025

Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice

Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, and is released into the extracellular space. Microglia are the first responders to the extracellular tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis and activate innate immune response gene expression by nuclear factor-kappa B (NF-{kappa}B). However, longitudinal NF-{kappa}B activation in tauopathies and whether pathological tau (pTau) contributes to NF-{kappa}B activity is unknown. Here, we tau oligomers from human Alzheimers disease brain (AD-TO) activate NF-{kappa}B in mouse microglia and macrophages reducing the I{kappa}B via promoting its secretion in the extracellular space. NF-{kappa}B activity peaks at 9- and 11-months age in PS19Luc+ and hTauLuc+ mice, respectively. Reducing pTau via pharmacological (DOX), genetic (Mapt-/-) or antibody-mediated neutralization (immunization with pT181-Q{beta} vaccine) reduces NF-{kappa}B activity, and together suggest pTau is a driver of NF-{kappa}B and chronic neuroinflammation tauopathies. SummaryNeuronal tau activates microglial NF-{kappa}B constitutively by secreting its inhibitor I{kappa}B. NF-{kappa}B activation in PS19Luc+ and hTauLuc+ mice peaks at 9- and 11-months of age, respectively. Neutralizing pTau with pT181-Q{beta} vaccine (targeting phosphorylated threonine 181 tau) alleviates NF-{kappa}B activity in tauopathy mice.

neuroscience↗

bioRxiv2025

Establishment of a second-generation transgenic marmoset model of polyglutamine disease recapitulating neurological symptoms and pathology

Neurodegenerative diseases, including polyglutamine diseases, remain a major clinical challenge, partly because of limited animal models that recapitulate human disease. Here, we describe a second-generation transgenic marmoset model of spinocerebellar ataxia 3 (SCA3), a polyglutamine disease, which stably expresses expanded CAG repeats in ATXN3. All five offspring of the founder marmoset harbored the transgene with reduced transgene integration sites and without repeat instability or genetic mosaicism, offering improved construct validity. Three of the five marmosets developed progressive motor impairments that segregated into two distinct phenotypes: early onset with rapid progression and late onset with mild progression, accompanied by corresponding patterns in body weight gain and grip strength. Pathological analysis revealed cerebellar Purkinje cell loss, spinal cord neurodegeneration, and widespread intranuclear inclusions. The severity of motor phenotypes correlated with transgene expression levels in disease-relevant brain regions, including the cerebellum, spinal cord, and striatum. By overcoming the common translational limitations of rodent systems, our second-generation model offers a powerful platform for investigating disease mechanisms and testing potential therapeutic interventions. Our results advance the utility of transgenic marmosets as clinically relevant models of neurodegenerative diseases. Summary StatementSecond-generation transgenic marmoset models of spinocerebellar ataxia 3 replicated the progressive motor deficits and neuropathology of the founder marmoset, providing a powerful platform for studying disease mechanisms and developing therapies.

neuroscience↗

bioRxiv2025

Sustained epithelial interferon signaling modulates incomplete pathologic response in colorectal cancer

Background & AimsPatients with colorectal cancer have heterogeneous clinical responses to chemotherapy, although clinical guidelines advise little variability in treatment selection based on molecular tumor features. Precision oncology research typically utilizes patient-derived tumor organoids (PDTO) to predict clinical outcomes, but such efforts are often not directed towards identification of molecular factors underlying differential responses to therapy. MethodsBulk RNA-sequencing was performed on treatment-naive PDTOs, and gene expression data was combined to drug sensitivity data to identify transcriptomic features associated with low in vitro sensitivity to chemotherapy. Whole-exome sequencing was performed on primary tumors to infer the somatic mutations of PDTOs and used to identify somatic mutations associated with differential in vitro drug responses. Publicly available gene expression and drug sensitivity data sets were used to validate the results. RNA interference was used for functional validation. ResultsPDTOs with low chemosensitivity had high JAK-STAT pathway activity resulting from high expression of interferon-stimulated genes. Evidence from single-cell RNA-sequencing confirmed chemotherapy-induced expression of interferon-stimulated genes in epithelial cells of cancers with partial response. EPSTI1 knockdown decreased cancer cell viability and sensitized cells to chemotherapy. ConclusionsSustained interferon signaling in epithelial cancer cells contributes to incomplete pathologic response in colorectal cancer. The findings highlight the potential of JAK-STAT inhibition or TRAIL pathway activation to enhance chemotherapy efficacy. Future studies investigating pharmacologic modulation of these pathways in preclinical CRC models are needed to determine their viability as therapeutic targets.

cancer biology↗

bioRxiv2025

Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology

BackgroundSynapses are essential for learning and memory, and their loss predicts cognitive decline in Alzheimers disease (AD). Synaptic loss is associated with excitotoxicity, neuroinflammation, amyloid-{beta}, and tau pathology, but the molecular mechanisms remain unclear. There is an urgent need to identify new targets to modify the disease and slow synaptic loss and cognitive decline. This study examines if calcium-dependent phospholipase A2 (cPLA2) is implicated in AD synaptic loss. cPLA2 catalyzes membrane phospholipids to release arachidonic acid, which can be metabolized into inflammatory eicosanoids. MethodscPLA2 levels were examined in synaptosomes isolated from the postmortem frontal cortex of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia from the Religious Orders Study (ROS). Eicosanoids in synaptosomes were analyzed using lipidomics. Immunofluorescent staining investigated cPLA2 interactions with synaptic markers. Human iPSCs-derived neurons were used to study cPLA2 overactivation after exposure to amyloid-{beta} 42 oligomers (A{beta}42O), its relationships with synaptic markers, and the effects of cPLA2 inhibitors. ResultsWe observed elevated cPLA2 (cPLA2 and cPLA2{beta}) in AD synaptosomes and positive correlations with postsynaptic density protein 95 (PSD-95) and cognitive dysfunction. Eicosanoids were increased in AD synaptosomes and correlated with cPLA2, indicating cPLA2 activity at synapses/synaptosomes. Phosphorylated cPLA2 (p-cPLA2) colocalized with PSD-95 in synaptosomes, and with postsynaptic Ca2+/calmodulin-dependent protein kinase II (CaMKII) and dendritic microtubule-associated protein 2 (MAP2) in NCI and AD brains, where their levels were reduced in AD. P-cPLA2 colocalizes with MAP2 at the neuronal soma associated with neuritic plaques and neurodegeneration in AD. A{beta}42O activates cPLA2 in human iPSCs-derived neurons, leading to p-cPLA2 relocation from the cytosol to synaptic and dendritic sites to colocalize with CaMKII and MAP2, resulting in their reduction. P-cPLA2 also colocalized with PSD-95 in A{beta}42O-exposed neurons, accompanied with increased PSD-95 intensity at soma membrane. These processes were reversed by the cPLA2 inhibitor ASB14780. ConclusionscPLA2 overactivation at synapses, dendrites, and excitatory neuronal somas is associated with synaptic loss, neuritic plaques and neurodegeneration, potentially contributing to cognitive decline in AD. Future research needs to explore the role of cPLA2 as a disease-modifying target for AD.

neuroscience↗

bioRxiv2025

Pathological calcium influx through amyloid beta pores disrupts synaptic function

Alzheimers disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-{beta} (A{beta}) oligomers disrupt calcium (Ca2+) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca2+ dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca2+ dynamics to examine how A{beta} pore activity alters exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that A{beta} pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while temporally brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that A{beta} pores and FAD-driven ER Ca{superscript 2} dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca{superscript 2} microdomains to create complex patterns of disruptions. This coupling creates feedback loops that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca2+ dysregulation, providing new mechanistic insights into the progressive nature of A{beta}-driven synaptic failure in AD.

neuroscience↗

bioRxiv2025

The β-amyloid oligomer Aβ*56 is associated with Alzheimer's dementia independently of amyloid pathology

The amyloid cascade hypothesis posits that {beta}-amyloid (A{beta}) oligomers (A{beta}o) play a key role in the pathogenesis of Alzheimers disease (AD). A{beta}o are believed to contribute to dementia in AD, and more than a dozen have been identified. While some oligomers are associated with amyloid plaques, others--such as A{beta}*56--are not. It remains unclear whether these plaque-independent oligomers contribute to dementia. A{beta}*56 is a non-fibrillar, sodium dodecyl sulfate-stable, brain-derived type of A{beta}o that impairs memory in mice. We recently confirmed and extended the characterization of A{beta}*56 in AD mouse models and identified two variants, namely A{beta}(40)*56 and A{beta}(42)*56 containing canonical A{beta}(1-40) and A{beta}(1-42), respectively. To examine the role of A{beta}*56 in dementia, we measured A{beta}*56 in elderly individuals--selected for equivalent levels of amyloid plaques--with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. Using immunoprecipitation (IP), western blotting (WB), size exclusion chromatography, and conformation-sensitive antibodies, we confirmed the presence of A{beta}(40)*56 and A{beta}(42)*56 in human brains. Using IP/WB coupled with densitometry-based semi-quantitative analysis, we found that levels of both A{beta}*56 variants were elevated in AD dementia compared to NCI and MCI and correlated inversely with various measures of memory and cognition. Furthermore, mediation analyses showed that these associations were mediated by phosphorylated tau at serine 202 and threonine 205 (ptau 202/205)-containing neurofibrillary tangles. These findings support an association between A{beta}*56 and AD dementia independently of amyloid pathology. The results are significant because they suggest that targeting A{beta}*56 in patients could provide additional cognitive benefits beyond those achieved by current anti-A{beta} therapies that focus on removing amyloid plaques.

biochemistry↗

bioRxiv2025

Brainstem pathology in human narcolepsy: Neurodegeneration in the locus coeruleus in narcoleptic humans, but not in genetically narcoleptic mice or dogs

Our earlier study led to the conclusion that human narcolepsy with cataplexy was caused by the loss of forebrain hypocretin (orexin) neurons in the hypothalamus. We now report that humans having narcolepsy with cataplexy also have a 46% decrease in the number and an 18% increase in the size of brainstem neuromelanin-pigmented locus coeruleus (LC) neurons and increased microglial activity in LC. However, no such changes are observed in the LC of hypocretin peptide depleted narcoleptic mice, hypocretin neuron depleted orexin-tTA/TetO-DTA (orexin-DTA) narcoleptic mice or in narcoleptic dogs. Sodium oxybate, an effective treatment for narcolepsy, decreased the size of LC norepinephrine neurons and increased the number and size of LC microglial cells in mice. Our results indicate that the autoimmune process believed to cause human narcolepsy affects both forebrain Hcrt neurons and brainstem LC norepinephrine cells. Addressing both forebrain and brainstem pathologies may improve understanding of, and treatments for, human narcolepsy.

neuroscience↗

bioRxiv2025

C9orf72 ALS-causing mutations lead to nucleoporin Nup107 aggregation and subsequent pathological changes

Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by motor neuron degeneration. Hexanucleotide repeat expansions in the C9orf72 gene, the most common genetic cause of ALS (C9-ALS), drive toxicity through different mechanisms. These pathological changes include alterations in stress granules (SGs), ribonucleoprotein complexes formed under stress conditions. Here, we show that G3BP1, a core component of SGs, aberrantly interacts with the nucleoporin Nup107 in motor neurons derived from patient iPSCs carrying C9orf72 mutations. Moreover, Nup107 colocalizes with SGs and aggregates in C9-ALS motor neurons. Notably, knockdown of the C. elegans ortholog of Nup107 alleviates ALS-associated phenotypes in worm models, including reduced lifespan and motility. Our findings provide insights into C9-ALS pathogenesis and identify Nup107 as a potential therapeutic target.

cell biology↗

bioRxiv2025

Molnupiravir inhibits Bourbon virus infection and disease-associated pathology in mice

Bourbon virus (BRBV) is an emerging tick-borne virus that can cause severe and fatal disease in humans. BRBV is vectored via the Amblyomma americanum tick, which is widely distributed throughout the central, eastern, and southern United States. Serosurveillance studies in Missouri and North Carolina identified BRBV-neutralizing antibodies in approximately 0.6% of tested individuals. To date, no specific antiviral therapy exists. Molnupiravir, an antiviral drug with oral bioavailability, has shown broad-spectrum antiviral activity against RNA viruses, including SARS-CoV-2. Here, we investigated the antiviral activity of molnupiravir against BRBV infection in cell culture and a mouse model of BRBV disease. Molnupiravir suppressed BRBV production in cells. In vivo, pre-exposure administration of molnupiravir protected susceptible type I interferon receptor knockout (Ifnar1-/-) mice against lethal BRBV infection. The protection by molnupiravir was associated with lower virus burden in mouse tissues, improvement of T cell (CD4+, CD8+) and B cell (follicular) profiles in the spleen, improvement of severe thrombocytopenia, and reduced pathology in the spleen and liver of BRBV-infected animals. Finally, therapeutic administration of molnupiravir starting 24 or 48 hours after infection ameliorated weight loss, clinical signs of disease, and lethality associated with BRBV infection. Overall, our experiments suggest that molnupiravir as a potential antiviral therapy for evaluation in humans with BRBV infections.

microbiology↗

bioRxiv2025

Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell-based microfluidic platforms

Retinal ganglion cells (RGCs) are highly compartmentalized cells, with long axons serving as the sole connection between the eye and the brain. RGC degeneration in injury and/or disease also occurs in a compartmentalized manner, with distinct injury responses in axonal and somatodendritic compartments. Thus, the goal of this study was to establish a novel microfluidic-based platform for the analysis of RGC compartmentalization in health and disease states. Human pluripotent stem cell (hPSC)-derived RGCs were seeded into microfluidics, enabling the recruitment and isolation of axons apart from the somatodendritic compartment. Initial studies explored axonal outgrowth and compartmentalization of axons and dendrites. We then compared the differential response of RGCs differentiated from hPSCs carrying the OPTN(E50K) glaucoma mutation with isogenic control RGCs in their respective axonal and somatodendritic compartments, followed by analysis of axonal transport. Further, we explored the axonal transcriptome via RNA-seq, focusing on disease-related axonal differences. Finally, we established models to uniquely orient astrocytes along the axonal compartment combined with modulation of astrocyte reactivity as a pathological feature of neurodegeneration. Overall, RGC culture within microfluidic chips allowed enhanced cell growth and maturation, including long-distance axonal projections and proper compartmentalization, while patient-specific RGCs exhibited axonal outgrowth deficits as well as decreased rate of axonal transport. Finally, the induction of astrocyte reactivity uniquely along the proximal region of RGC axons led to the onset of neurodegenerative phenotypes in RGCs. These results represent the first study to effectively recapitulate the highly compartmentalized properties of hPSC-derived RGCs in healthy and disease states, providing a more physiologically relevant in vitro model for neuronal development and degeneration.

neuroscience↗

bioRxiv2025

Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice

Acetaminophen (APAP) produces analgesia through mechanisms that remain poorly understood. Here, we tested the hypothesis that APAP-induced suppression of pathological pain is associated with cannabinoid receptors and activity of enzymes regulating endogenous lipids (diacylglycerol lipase, DAGL; monoacylglycerol lipase, MAGL) including endocannabinoids. APAP suppressed mechanical hypersensitivity in mouse models of post-surgical and inflammatory pain and the DAGL inhibitors (RHC-80267, DO34) and MAGL inhibitor JZL184 blocked APAPs analgesic effects. Global (rimonabant, AM251) but not peripherally restricted (AM6545) cannabinoid receptor antagonists prevented APAP-induced analgesia. APAP increased corticosterone levels >2-fold and reduced prostaglandins >5-fold across the brain and in the paw skin. In addition, APAP reduced up to 39% of signaling lipids detected in the targeted screen in CFA-treated subjects in a tissue-dependent manner. These observations suggest that APAP plays a wider role in endogenous lipid signaling than previously hypothesized and provides novel insight into mechanisms of action.

neuroscience↗

bioRxiv2025

Chronic compression drives macrophages toward a pathological pro-tumor state

Macrophages comprise a significant portion of the glioblastoma tumor microenvironment and are essential in promoting immunosuppression and tumor progression. Solid tumors such as glioblastoma generate solid stress as they expand, creating a compressive microenvironment for mechanosensitive immune cells including macrophages. Macrophages are known to respond to various mechanical stimuli but have not yet been studied in the context of chronic compression observed in growing tumors. Here, we used a custom in vitro compression system to elucidate the effects of compressive solid stress on murine macrophages. We found that macrophages have significant morphological, transcriptional, metabolic, and functional responses to compression. These changes corresponded to both canonical pro- and anti-inflammatory macrophage states. The gene expression signatures of compressed macrophages more closely resembled those of glioma-associated macrophages known to be associated with worse patient outcomes. These results indicate that compression alone, independent from tumor cell-derived biochemical factors, may contribute to the pathological tumor-associated macrophage phenotype. This could represent a vicious cycle of tumor immunomechanics and mechano-immunology. Targeting solid stress in tumors or the response to solid stress by macrophages may interrupt this feedback loop to help normalize the tumor immune microenvironment and improve glioblastoma response to immunotherapy.

immunology↗

bioRxiv2025

Clinical, Biological and Pathological Investigation of Bovine Lymphocyte Intestinal Retention Deficit (BLIRD): a new genetic disorder affecting life expectancy and immunity in Holstein dairy cattle

Dozens of missed recessive loci affecting homozygous carriers life expectancy were recently reported. This article details the clinical, biological and pathological manifestations of a new bovine genetic disorder caused by an ITGB7 p.G375S point mutation in the French Holstein cattle breed. Our thorough study involved database analysis of genotyped cattle and a series of case-control investigations of forty homozygous mutants for the causative variant. These mutants had a significantly shorter lifespan (fewer than 64% surviving past three years vs. 87% in controls), along with reduced body weight, daily weight gain, and dairy performance. The mutation did not affect most biochemical parameters, but a marked lymphocytic leucocytosis, moderate eosinophilia and differences in faecal microbiota were observed. Although non-pathognomonic symptoms may be confused with those of common environmental diseases, the blood profile effectively identified suspected carriers who developed ill-thrift and poor growth as heifers. Our research demonstrates that the bovine ITGB7 p.G375S substitution leads to reduced longevity, poor condition and production, in most homozygous carriers. Furthermore, this spontaneous model may help to refine the functions of the {beta}7 integrin in immune homeostasis and defence.

immunology↗

bioRxiv2025

Gut miRNA regulates gut microbiome and Alzheimer pathology in App-knock-in mice

Alzheimers disease (AD) alters the gut microbiome. It remains unclear whether manipulation of miRNA could modulate the gut microbiome and AD pathologies. Depletion of gut miRNA in App-knock-in mice by conditional knockout of Dicer1 gene in intestinal epithelial cells: 1) decreased the absolute number and changed the composition of bacteria in both the gut and brain; 2) reduced cerebral A{beta} load by inhibiting {beta}-secretase activity and increasing the expression of LRP1 and ABCB1 at the blood-brain barrier; 3) increased Il-10 transcription and decreased the transcription of Ccl-2 gene, and that of Ndufa2 and Ndufa5 genes encoding mitochondrial respiratory enzymes in the brain; and 4) induced anxiety symptoms without affecting cognitive function in AD mice. Thus, manipulating miRNA in the gut can modify AD pathogenesis. Future studies should focus on identifying AD-specific miRNAs in the gut that can be therapeutically exploited (e.g. by oral administration) to prevent the progression of AD.

neuroscience↗

bioRxiv2025

Repetitive mild traumatic brain injury causes neuronal damage in the APP/PS1 mouse model of Alzheimer's disease without an enduring impact on amyloid pathology, sleep, or epileptiform activity

Traumatic Brain Injury (TBI) is a known risk factor for Alzheimers disease and related neurodegenerative diseases. Sleep disturbances and epileptiform abnormalities can appear after TBI and may contribute to the development of neuropathology. In this study, we characterized sleep, epileptiform activity, and neuropathology after repetitive mild traumatic brain injury (rmTBI) in a mouse model of Alzheimers disease. We used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) to deliver rmTBI or sham (control) treatment to 6-month-old APP/PS1 mice (N=19). One month post-injury, we implanted electroencephalogram (EEG) and electromyographic (EMG) electrodes, recorded for 72 hours, and then collected brain tissue and blood plasma. Our assessment of sleep architecture showed that time spent in vigilance state was not affected by the rmTBI one month post-injury; however, power spectra analysis showed a shift towards higher frequencies in the rmTBI group during non-rapid eye movement (NREM) sleep. Epileptiform activity did not differ between sham and rmTBI. Compared to sham controls, the rmTBI group showed higher neurofilament light (NF-L), but not glial-fibrillary acidic protein (GFAP) in blood plasma and no change in A{beta} pathology. These results indicate sustained neurological injury in the APP/PS1 mice one month after rmTBI without affecting amyloid deposition in the brain. Our study suggests that rmTBI can induce neural injury without causing enduring sleep disruption, seizures, and exacerbation of amyloidosis in the APP/PS1 mouse model.

neuroscience↗

bioRxiv2025

Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer's-like pathology

Aging is the strongest risk factor for cognitive decline and Alzheimers disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Canas potential to combat brain aging and AD through sex-specific mechanisms.

neuroscience↗