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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2024

Tet2 loss suppress α-synuclein pathology by stimulating ciliogenesis

There are no approved treatments that slow Parkinsons disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of -synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and rescued the accumulation of -synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of Tet2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

neuroscience↗

bioRxiv2024

Seed-competent alpha-synuclein pathology in metachromatic leukodystrophy: the expanding spectrum of alpha-synucleinopathy in sphingolipidoses

Metachromatic leukodystrophy (MLD) is a rare - typically paediatric - sphingolipid storage disorder resulting from bi-allelic pathogenic variants in the ARSA gene, encoding the lysosomal arylsulphatase A (ASA). Heterozygous variants in ARSA are associated with risk of Lewy body diseases (LBD), a group of age-associated neurodegenerative disorders characterised by the accumulation of the protein -synuclein; however, no study has yet determined whether -synuclein with putative pathological features is observed in MLD brain tissue. We examined post-mortem brain tissue from MLD cases (N=5, age 2-33) compared to matched control cases using histological approaches and -synuclein seeding amplification assay (SAA). Juvenile-onset MLD cases exhibited granular -synuclein deposits in neurons of regions prone to neuronal pathology in MLD, and seed-competent conformers that generated atypical short, twisted fibrils on SAA. In contrast, infantile-onset MLD cases gave only variably positive reactions on SAA. In summary, this study suggests MLD cases manifest -synuclein pathology reminiscent of that observed in LBD, even in juvenile populations, further expanding the spectrum of sphingolipid storage disorders associated with the aggregation of -synuclein. These findings have important implications for understanding the disease process of both LBD and MLD, potentially highlighting novel pathways for therapeutic interventions in both conditions.

neuroscience↗

bioRxiv2024

Long-read transcriptomic identification of synaptic adaptation to amyloid pathology in the App(NL-G-F) knock-in mouse model of the earliest phase of Alzheimer's disease

Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimers disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the AppNL-G-F knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-{beta}. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-{beta} at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the AppNL-G-F knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-{beta} during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.

genetics↗

bioRxiv2024

The speed limits for tau pathology progression in Alzheimer's disease

ObjectiveTo examine interactive effects of modifiable factors, genetic determinants and load-dependent pathology effects on tau pathology progression. MethodsData of 162 amyloid-positive individuals were included, for whom longitudinal [18F]AV-1451-PET scans, baseline information on global amyloid load, ApoE4 status, body-mass-index (BMI), hypertension, education, neuropsychiatric symptom severity and demographic information were available in ADNI. All [18F]AV-1451 PETs were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects) and subsequently thresholded (z-score > 1.96) and converted to volume-maps. Based on these volume-maps, tau-changes over time were assessed in terms of 1) tau-speed (i.e. newly affected volume at follow-up), and 2) tau-level-rise (i.e. tau increase in previously affected volume). These two measures were entered as dependent variables in separate linear mixed effects models including four baseline risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), baseline amyloid, tau-volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the four modifiable factors on either tau-speed or tau-level-rise, respectively. ResultsFaster tau-speed was linked to higher BMI, female sex, ApoE4-status, and baseline tau-volume. The effect of baseline tau-volume on tau-speed was driven by greater global amyloid burden. In terms of tau-level-rise, we observed that lower hypertension and BMI were linked to a slower increase in tau burden. A load-dependent effect of baseline amyloid and tau burden was found. Higher amyloid and BMI as well as lower education and higher tau burden were linked to greater tau-level-rise. ConclusionEducation, BMI and hypertension differentially influence tau speed and level rise by its interaction with initial pathological burden. Timely modification of these factors may overall slow taus progression.

neuroscience↗

bioRxiv2024

Protective variant in PLCgamma2 mitigates Alzheimer's disease associated pathology via enhancing beneficial microglia functions

BackgroundPLC{gamma}2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimers disease. Recently, it was shown to decrease {beta}-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLC{gamma}2-P522R variant in a less aggressive mouse model of AD as well as to assess the underlying mechanisms at the molecular and cellular level using mouse and human microglia models. MethodsThe effects of the protective PLC{gamma}2-P522R variant on microglia activation, AD-related {beta}-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLC{gamma}2-P522R knock-in mice crossbred with APP/PS1 AD model mice. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLC{gamma}2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLC{gamma}2-P522R variant carriers were employed to translate the key findings to human cells. ResultsOur results demonstrate that the PLC{gamma}2-P522R variant reduced brain {beta}-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLC{gamma}2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around {beta}-amyloid plaques, leading to reduced {beta}-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLC{gamma}2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLC{gamma}2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLC{gamma}2-P522R increased mitochondrial respiration in iPSC-derived microglial cells. ConclusionsTogether, these findings suggest that PLC{gamma}2-P522R variant exerts protection against AD-associated {beta}-amyloid and neuronal pathologies via enhancing microglial barrier formation around {beta}-amyloid plaques and suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLC{gamma}2-P522R variant are mediated through an anti-ageing mechanism.

neuroscience↗

bioRxiv2024

SENP2-based N-terminal truncation of α-synuclein in Lewy pathology propagation

-Synuclein (Syn) is a major component of Lewy bodies (LBs) and Lewy neurites (LNs) which are pathological features of Parkinsons disease (PD) and Dementia with Lewy bodies. In the PD brain, with disease progression, LB/LN formation is propagated from the lower brainstem to the cerebral cortex. Prion-like cell-to-cell seed-transmission has been implicated as an underlying mechanism for Lewy-pathology propagation. However, the biochemical properties and production mechanism of those pathogenic seeds are unelucidated. In this study, we ascertained that the seeds released from pathological neurons that harbour LB/LN-like aggregates have the N-terminally truncated form of Syn. This N-terminal truncation is directly catalysed by SENP2, which is a well-known deSUMOylation enzyme. After SENP2 processing of recombinant Syn, the SDS-resistant high-molecular oligomer formation was promoted in vitro. Inhibition of SENP2 activity suppressed aggregate formation and propagation in cultured neurons and mouse brains. Thus, SENP2 might be a novel therapeutic target in LB diseases.

neuroscience↗

bioRxiv2024

Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinsons disease reveals unique and shared pathological features.

IntroductionPrimary synucleinopathies, such as Parkinsons disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders with some shared clinical and pathological features. Aggregates of alpha-synuclein (syn) phosphorylated at serine 129 (PSER129) are the hallmark of synucleinopathies, which for PD/DLB are found predominantly in neurons (Neuronal cytoplasmic inclusions "NCIs"), but for MSA, aggregates are primarily found in oligodendroglia (Glial cytoplasmic inclusions "GCIs"). It remains unclear if the distinct pathological presentation of PD/DLB and MSA are manifestations of distinct or shared pathological processes. We hypothesize that the distinct synucleinopathies MSA and PD/DLB share common molecular features. MethodsUsing the in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated syn-interactomes (BAR-PSER129) and total syn-interactomes (BAR-MJFR1) between MSA (n=5) and PD/DLB (n=10) in forebrain and midbrain structures. ResultsFor BAR-PSER129 and BAR-MJFR1 captures, syn was the most significantly enriched protein in PD/DLB and MSA. In PD/DLB, BAR-PSER129 identified 194 syn-aggregate-interacting proteins, while BAR-MJFR1 identified 245 syn interacting proteins. In contrast, in the MSA brain, only 38 and 175 proteins were identified for each capture, respectively. When comparing MSA and PD/DLB, a high overlap (59.5%) was observed between BAR-MJFR1 captured proteins, whereas less overlap (14.4%) was observed for BAR-PSER129. Direct comparison between MSA and PD/DLB revealed 79 PD/DLB-associated proteins and only three MSA-associated proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed PD/DLB interactions were dominated by vesicle/SNARE-associated pathways, in contrast to MSA, which strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathways in MSA. A common network of 26 proteins, including neuronal-specific proteins (e.g., SNYGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of disease or BAR target protein. ConclusionSynucleinopathies have divergent and convergent syn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SNYGR3 (i.e., a neuronal protein), between MSA and PD/DLB suggest neuronal axons origin for both diseases. In conclusion, we provide syn aggregates protein interaction maps for two distinct synucleinopathies.

neuroscience↗

bioRxiv2024

Lipidomic Profiling Reveals Shared and Distinct Pathological Signatures in Sporadic Parkinson's Disease and GBA Mutation Carriers: Implications for Disease Mechanisms

Parkinsons Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein-lipid inclusions, containing alpha-synuclein, neuronal cell loss and disruptions in lipid metabolism such as those associated with GBA mutations. GBA mutations are together an important genetic risk factor for PD and are associated with a decrease in glucocerebrosidase, a lysosomal glycoprotein encoded by GBA, increase in alpha-synuclein and changes in sphingolipids levels and composition. However, the extent of lipid metabolism disruptions associated to PD and their contributions to disease progression remain unclear. In this study, we used a combination of biochemical and lipidomic analyses of amygdala from healthy controls (HC) and people with sporadic (sPD) or GBA-associated PD (PD-GBA) to investigate the correlation between alpha-synuclein, glucocerebrosidase and lipids. We found extensive metabolic remodelling of brain lipids, including increased free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids in amygdala from people with sPD and disease duration above 30 years (sPD>30y) and from people with PD carriers of a GBA risk mutation (PD-GBArisk) relative to HC. The levels of free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids all correlated positively with pathological S and negatively with GCase activity. In contrast, the levels of phosphatidylethanolamine and cardiolipin only correlated positively with GCase activity. Moreover, we observed changes in the distribution of species for sphingolipids and glycerophospholipids in opposite directions for two categories of PD cases. We found a shift from short to long sphingomyelin and ceramide and from long to short phosphatidylserine and phosphatidylethanolamine in sPD>30y and PD-GBArisk cases and the opposite in sPD<10y and PD-GBAsevere cases. The relative proportion of lipid species affected in these samples all correlated with glucocerebrosidase activity and pathological alpha-synuclein levels. Together, these findings highlight the correlation between glucocerebrosidase, pathological alpha-synuclein and lipid levels in PD. Moreover, the identified opposite changes in lipid distribution for two categories of people with sPD and PD-GBA underscore the importance of patient stratification in clinical trials aiming at reverting PD-related lipid changes.

neuroscience↗

bioRxiv2024

Critical role for the TGF-β1/mTORC1 signalling axis in defining the transcriptional identity of CTHRC1+ pathologic fibroblasts

Fibrosis, defined as the abnormal deposition of extracellular matrix (ECM), represents the concluding pathological outcome in a number of inflammatory, immune-mediated and metabolic diseases. Recent single cell RNA-sequencing studies have highlighted the diversity and functional heterogeneity of fibroblast populations in multiple fibrotic conditions. These include a novel pathogenic population of high collagen-producing fibroblasts, characterised by expression of the secreted glycoprotein, collagen triple helix repeat containing 1 (CTHRC1). The cardinal pro-fibrotic mediator TGF-{beta}1 has been widely implicated in promoting fibrogenesis and is a potent inducer of CTHRC1 and COL1A1 expression. In addition to the canonical Smad signalling pathway, TGF-{beta}1-induced collagen I production is under critical regulatory control by the mTORC1/4E-BP1 signalling hub. Using pharmacological inhibition in combination with gene-editing approaches, we now demonstrate that the role of the mTORC1 axis extends to the regulation of over a third of all TGF-{beta}1 regulated matrisome genes. We provide further evidence that the global transcriptome of TGF-{beta}1-stimulated fibroblasts in vitro matches that of a subpopulation of the high collagen expressing CTHRC1+ pathological fibroblast population in the IPF lung. In contrast, the TGF-{beta}1 induced transcriptome of fibroblasts in which mTORC1 signalling is disrupted (by RPTOR gene editing using CRISPR-Cas9) does not map to any fibroblast population present in human control or fibrotic lung. Using the novel and selective mTORC1 inhibitor RMC-5552, we further demonstrate a direct functional link between mTORC1 signalling and the acquisition of key marker genes which define the CTHRC1+ fibroblast population in IPF. These data demonstrate, for the first time, a critical role for the mTORC1 signalling hub in determining the transcriptional identity of the CTHRC1+ pathological fibroblast population and provide strong scientific support for targeting mTORC1 as a therapeutic strategy in IPF and potentially other fibrotic conditions associated with dysregulated TGF-{beta}1 signalling in the fibrotic niche.

cell biology↗

bioRxiv2024

Counterfactual Diffusion Models for Mechanistic Explainability of Artificial Intelligence Models in Pathology

Deep learning can extract predictive and prognostic biomarkers from histopathology whole slide images. However, explainable artificial intelligence approaches widely used in digital pathology, such as attention heatmaps and class activation mapping, offer only limited interpretability regarding the features captured by classifiers. Here, we present MoPaDi (Morphing histoPathology Diffusion), a framework for generating counterfactual explanations for histopathology images that reveal which morphological or style features drive classifier predictions. MoPaDi combines diffusion autoencoders with task-specific multiple instance learning classifiers to manipulate images and flip predictions by modifying relevant features. We evaluated the framework on multiple datasets spanning colorectal, breast, liver, and lung cancers, including tissue type, cancer subtype, and biomarker (microsatellite instability) classification tasks. We assessed counterfactual explanations through quantitative analyses, pathologists evaluations, and independent foundation model-based classifiers. We found that MoPaDi was able to generate realistic counterfactual histopathology images, enabling pathologists to identify morphological features associated with the change in model predictions. Unlike conventional reviews of highly attended regions typical in digital pathology, MoPaDi explanations enabled pathologists to directly identify morphological features driving the classifiers predictions from a limited number of top-contributing tiles. Consistent with the literature, our biomarker classifier associated high microsatellite instability with mucinous differentiation, glandular patterns, and lymphocytic infiltration. Furthermore, MoPaDi revealed that changes in classifier predictions were mainly driven by morphological alterations rather than staining differences. Overall, MoPaDi is a practical framework for counterfactual explanations in computational pathology that reveals model-specific drivers of classification and increases trust in deep learning models.

bioinformatics↗

bioRxiv2024

Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimers Disease-linked pathologies in cultured human neurons

Abnormal increase in axonal lysosome abundance is associated with multiple neurodegenerative diseases including Alzheimers disease. However, the underlying mechanisms and disease relevance are not fully understood. We have recently identified RH1115 as a small molecule modulator of the autophagy-lysosomal pathway that regulates lysosome positioning in neurons. This allowed us to manipulate neuronal lysosome distribution including in axons and interrogate its contribution to both optimal neuronal functioning and to disease pathology. We demonstrate that the small molecule not only rescues aberrant buildup of both axonal autophagic and lysosomal intermediates but also reduces secreted A{beta}42 levels in human iPSC-derived neurons lacking the lysosomal adaptor, JIP3. We thus demonstrate that restoring efficient axonal lysosome transport has an anti-amyloidogenic effect in human neurons and is a promising therapeutic strategy for Alzheimers disease. Furthermore, we show that the small molecule enhances neuronal lysosome degradation, requires the lysosomal adaptor JIP4 to rescue the axonal lysosome pathology in the JIP3 KO neurons and increases levels of the JIP4-interacting lysosomal membrane protein, TMEM55B. Lastly, treatment with the small molecule led to a striking rescue of locomotor defects in JIP3 KO zebrafish larvae. Thus, we have identified a small molecule which can be impactful in neurodegenerative diseases that have a lysosomal pathology and have determined its molecular targets in modulating axonal lysosome abundance.

cell biology↗

bioRxiv2024

Top-down attention and Alzheimer's pathology impact cortical selectivity during learning,influencing episodic memory in older adults

Human aging affects the ability to remember new experiences, in part, because of altered neural function during memory formation. One potential contributor to age-related memory decline is diminished neural selectivity -- i.e., a decline in the differential response of cortical regions to preferred vs. non-preferred stimuli during event perception -- yet the factors driving variability in neural selectivity with age remain unclear. We examined the impact of top-down attention and preclinical Alzheimers disease (AD) pathology on neural selectivity during memory encoding in 156 cognitively unimpaired older participants who underwent fMRI while performing a word-face and word-scene associative memory task. Neural selectivity in face- and place-selective cortical regions was greater during events that were later remembered compared to forgotten. Critically, neural selectivity during learning positively scaled with memory-related variability in top-down attention, whereas selectivity negatively related to early AD pathology, evidenced by elevated plasma pTau181. Path analysis revealed that neural selectivity at encoding mediated the effects of age, top-down attention, and pTau181 on associative memory. Collectively, these data reveal multiple pathways that contribute to memory differences among older adults -- AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.

neuroscience↗

bioRxiv2024

Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies

The neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD, however, remain unresolved. Diverse disease models including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including CNTFR (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics. SIGNIFICANCE STATEMENTO_LIUnderstanding the cellular pathology of Frontotemporal Dementia linked to a GGGGCC expansion in the C9orf72 gene remains a challenge. C_LIO_LIThis study shows that undifferentiated patient-derived iPSCs exhibit hallmark FTD characteristics, including lysosome dysfunction and TDP-43 proteinopathy, and identifies dysregulated genes related to neurodegeneration. C_LIO_LIThese findings highlight patient-derived iPSCs as a valuable model for studying FTD pathology and for drug screening, potentially guiding future research in therapeutic development. C_LI

neuroscience↗

bioRxiv2025

Alpha-Synuclein co-pathology in Alzheimer's Disease drives tau accumulation

The molecular basis for accelerated cognitive decline seen in Alzheimers Disease (AD) cases presenting with cortical alpha-Synuclein (-Syn) co-pathology is not well understood. We show that such co-pathology brains express higher levels of microtubule-associated protein tau and that increasing -Syn expression is sufficient to drive tau accumulation. Our results reveal a hitherto unknown link between the pathogenesis of AD and Parkinsons Disease whereby tau and -Syn synergistically drive dementia-related pathology.

neuroscience↗

bioRxiv2025

The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E

Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2,500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated the orthologous NEFLE396K mutation in the mouse C57BL/6 background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.

neuroscience↗

bioRxiv2025

APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction

APOE4 is the leading genetic risk factor for Alzheimers disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimers onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimers pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigate whether and how APOE4 confers sensitivity to glucocorticoids, the main stress hormones. We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology in APOE4 mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimers pathogenesis in this population.

neuroscience↗

bioRxiv2025

Ketogenic Diet Enhances Cognitive-Behavioral Function and Hippocampal Neurogenesis While Attenuating Amyloid Pathology in Tg-SwDI Mice

The ketogenic diet (KD), characterized by high-fat, low-carbohydrate, and moderate protein intake, has gained attention for its therapeutic potential in patients with neurodegenerative diseases, including Alzheimers disease. Studies in Alzheimers rodent models report that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, amyloid-beta plaques and tau pathology. However, it is unknown whether KD can similarly benefit individuals with cerebral amyloid angiopathy (CAA), a prevalent condition in which amyloid accumulates in cerebral vessels. CAA is highly comorbid in patients with Alzheimers and, on its own, increases the risk of stroke, cognitive impairment, and dementia, yet no effective treatments currently exist. The objective of this study was to determine whether KD can improve cognitive-behavioral and neuropathological outcomes in a mouse model with CAA. Male Tg-SwDI mice were fed either a standard chow or KD from 3.5 to 7.5 months of age. Following [~]3 months of dietary intervention, glucose and ketone-body levels were assessed, then mice underwent a battery of behavioral tests to evaluate locomotor activity, anxiety-related behaviors, and cognition. Immunohistochemistry was performed to assess amyloid pathology, vascular density, neuroinflammation, white matter integrity, and hippocampal neurogenesis. In addition to KD inducing nutritional ketosis and achieving metabolic benefits, mice on KD exhibited increased activity, enhanced spatial learning and memory, and a trend toward improved spatial working memory. These cognitive benefits were accompanied by an attenuation of amyloid pathology and increased hippocampal neurogenesis. These findings suggest that a ketogenic diet may be safe and effective in Alzheimers and dementia patients with CAA.

neuroscience↗

bioRxiv2025

Formaldehyde induces and promotes Alzheimer's disease pathologies in a 3D human neural cell culture system

Alzheimers disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on A{beta} and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FAs role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in A{beta}40, A{beta}42, and phosphorylated tau levels. To further examine FAs role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated A{beta}40, A{beta}42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.

neuroscience↗