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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2025

Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in Human Brain Tissue

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and -synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to -synuclein pathology. Like the human brain, pathogenic -synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble -synuclein leading to a pathogenic transformation that seeds -synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

neuroscience↗

bioRxiv2025

Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model

Wild-type superoxide dismutase 1 (disSOD1) protein misfolding and deposition is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated the potential of the blood-brain-barrier-permeable copper delivery drug, CuATSM, to attenuate the misfolding and deposition of wild-type disSOD1, and associated neuron death, in a novel mouse model that expresses this pathology. Using proteomic and elemental mass spectrometry, together with biochemical and histological workflows, we demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. These data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder.

neuroscience↗

bioRxiv2025

Distinguish risk genes functioning at presynaptic or postsynaptic regions and key connectomes associated with pathological α-synuclein spreading

Previous studies have suggested that pathological -synuclein (-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: (1) How many and which connections in the connectome are necessary for predicting the progression of pathological -Syn? (2) How to identify risk gene that affects pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, we addressed these key questions with novel mathematical models. Strikingly, the spreading of pathological -Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. We further explored the genes that are responsible for the selective vulnerability of different brain regions to transmission to distinguish the genes that play roles in presynaptic from those in postsynaptic regions. Those risk genes were significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic regions. Gene regulatory network analyses were then conducted to identify key drivers of genes responsible for selective vulnerability and overlapping with Parkinsons disease risk genes. By identifying and discriminating between key gene mediators of transmission operating at presynaptic and postsynaptic regions, our study has demonstrated for the first time that these are functionally distinct processes.

neuroscience↗

bioRxiv2025

Casein kinase 1δ-regulated formation of GVBs induces resilience to tau pathology-mediated protein synthesis impairment

In Alzheimers disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs, however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that CK1{delta} activity is required for GVB formation. CK1{delta} is sequestered in the GVB during this process in an autophagy-dependent manner. We show that neurons with GVBs (GVB+) are resilient to tau-induced impairment of global protein synthesis and are protected against tau-mediated neurodegeneration. GVB+ neurons do not exhibit differential activation of proteostatic stress responses, but have increased ribosomal content. Importantly, unlike neurons without GVBs, GVB+ neurons fully retain the capacity to induce long-term potentiation-induced protein synthesis in the presence of tau pathology. Our results have identified CK1{delta} as a key regulator of GVB formation that confers a protective neuron-specific proteostatic stress response to tau pathology. These findings provide novel opportunities for targeting neuronal resilience in tauopathies. HighlightsO_LIGVB+ neurons are protected against tau-induced neurodegeneration C_LIO_LICK1{delta} activity is essential for the formation of GVBs C_LIO_LIGVB+ neurons are resilient to tau-induced impairment of protein synthesis C_LIO_LIGVB+ neurons retain the capacity for LTP-regulated protein synthesis C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/645932v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@cda628org.highwire.dtl.DTLVardef@157bcb8org.highwire.dtl.DTLVardef@126dbe6org.highwire.dtl.DTLVardef@2efe8f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A mouse model of early sporadic tau pathology induces neurogenic plasticity in the hippocampus

Alzheimers disease is characterized by widespread neurodegeneration and the accumulation of insoluble amyloid plaques and neurofibrillary tangles. However, at the earliest stages of the disease cell death and pathological tau are localized to the entorhinal cortex. In particular, the lateral entorhinal cortex, and its functions in object-related memory, are among the most vulnerable in aging. Notably, the entorhinal cortex projects directly to the dentate gyrus subregion of the hippocampus, where neurogenesis proceeds throughout adult life. Immature, adult-born neurons provide a robust source of plasticity to the entorhinal-dentate pathway and they may be uniquely responsive, or vulnerable, to early entorhinal tau pathology. To test this, we injected a human tau-expressing recombinant adeno-associated virus into the lateral entorhinal cortex and used AsclCreER mice to birthdate downstream dentate neurons born in early postnatal development or adulthood. Consistent with known roles in neurodegeneration, lateral entorhinal tau expression caused a loss of mushroom spines in downstream dentate neurons and reduced dendritic complexity of adult-born neurons in male mice. Presynaptic tau also increased neurogenesis levels and increased the density of thin spines on adult-born neurons. Despite these morphological effects, tau did not alter synaptic strength or the magnitude of long-term potentiation at entorhinal synapses onto adult- or developmentally-born neurons. Thus, in a novel model of early sporadic tau pathology, there are morphological changes consistent with neurodegeneration but also compensatory neuroplastic changes, caused by neurogenesis. Since immature neurons have also been identified in the human dentate gyrus, a similar neurogenic plasticity may help maintain entorhinal-hippocampal formation in pathological aging.

neuroscience↗

bioRxiv2025

Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4

INTRODUCTIONIn neurodegenerative dementias, the co-occurrence and interaction of A{beta}, tau, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODSWe analyzed 480 post-mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among A{beta}, tau, LATE-NC, -synuclein, other age-related lesions, and APOE {varepsilon}4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTSA{beta}, tau, LATE-NC, and amygdala-predominant -synuclein pathology were highly interconnected. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and -synuclein, while APOE {varepsilon}4 was mainly associated with extracellular and capillary A{beta}. DISCUSSIONAlthough Alzheimers pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.

neuroscience↗

bioRxiv2025

Pathological Mechanisms of Motor Dysfunction in Familial Danish Dementia: Insights from a Knock-In Rat Model

Familial Danish Dementia (FDD) is a rare autosomal dominant neurodegenerative disorder caused by a mutation in the integral membrane protein 2B (ITM2b) gene. Clinically, FDD is characterized by cerebral amyloid angiopathy (CAA), cerebellar ataxia, and dementia. Notably, FDD shares several neuropathological features with Alzheimers disease (AD), including CAA, neuroinflammation, and neurofibrillary tangles. In this study, we investigate the pathological mechanisms linking CAA, white matter damage, and motor dysfunction using a recently developed FDD knock-in (FDD-KI) rat model. This model harbors the Danish mutation in the endogenous rat Itm2b gene, along with an App gene encoding humanized amyloid-{beta} (A{beta}). Our analysis revealed substantial vascular Danish amyloid (ADan) deposition in the cerebellar subpial and leptomeningeal vessels of FDD-KI rats, showing an age-related increase comparable to that observed in human FDD patients. Additionally, vascular A{beta} deposits (A{beta}-CAA) were present in FDD-KI rats, but A{beta}-CAA patterns showed some differences between species. Motor function assessments in FDD-KI rats demonstrated age-accelerated motor deficits and gait abnormalities, mirroring the clinical characteristics of FDD patients. To further explore the mechanisms underlying these deficits, we examined cerebellar pathology and found age-related myelin disruption and axonal fiber loss, consistent with postmortem human FDD pathology. Cerebellar demyelination appeared to be driven by neuroinflammation, marked by increased microglial/macrophage activation in response to vascular amyloid deposition. Additionally, we observed extravascular fibrinogen leakage, indicating widespread vascular permeability in both white and gray matter, with fibrinogen deposits surrounding amyloid-positive vessels in aged FDD-KI rats and postmortem FDD cerebellum. These findings suggest that this FDD-KI rat model is the first animal model to recapitulate key neuropathological features of human FDD patients, including both ADan- and A{beta}-type CAA, neuroinflammation, and white matter lesions--pathologies that may underlie the motor and gait impairments seen in the disease.

neuroscience↗

bioRxiv2025

Telomere-driven senescence accelerates tau pathology, neuroinflammation and neurodegeneration in a tauopathy mouse model

BackgroundAlthough the connection between aging and neurodegenerative pathologies like Alzheimers disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal link has been established between senescence and AD-related tauopathy. MethodsTo investigate the role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc-/-) senescent mouse model with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, we employed Western blot and immunostaining analyses to investigate the expression of tau-related neuropathological features within a senescent context. ResultsWe found that the brains of 6-and 9-month-old Terc-/- mice exhibit significant telomere attrition and signs of cellular senescence. Introducing a senescent phenotype in a tauopathy mouse model resulted in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this was associated with enhanced tau truncation and aggregation. These pathological changes were accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. ConclusionsOverall, our findings place senescence as a key upstream regulator of tau pathology, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.

neuroscience↗

bioRxiv2025

Features fusion or not: harnessing multiple pathological foundation models using Meta-Encoder for downstream tasks fine-tuning

The emergence of diverse pathological foundation models has empowered computational pathology tasks, including tumor classification, biomarker prediction, and RNA expression prediction. However, variations in model architecture and data sources lead to inconsistent downstream performance and complicate centralized training. Specifically, the lack of data sharing makes retraining foundation models with pooled data infeasible. Alternatively, the release of model parameters enables combining multiple models during fine-tuning. Inspired by the meta-analysis method, we propose the Meta-Encoder framework, which integrates features from multiple foundation models to generate a comprehensive representation, improving downstream fine-tuning task performance. Comparative experiments demonstrate that Meta-Encoder is more effective than individual foundation models, with its strengths more pronounced in handling complex tasks. While single models may perform sufficiently well for simple tasks, Meta-Encoder can match or even surpass the best-performing single model, alleviating concerns over model selection. Moderately challenging tasks benefit from Meta-Encoders concatenation or self-attention strategies, with the latter demonstrating superior performance in more challenging scenarios. For highly complex tasks, such as high-dimensional gene expression prediction, self-attention proves to be the most effective Meta-Encoder strategy, balancing feature integration and computational efficiency. For three patch-level spatial gene expression prediction tasks (HEST-Benchmark, CRC-inhouse, and Her2ST), the self-attention strategy improved the Pearson correlation by 38.58%, 26.06%, and 20.39%, respectively, compared to the average performance of three patch-level single models. Similarly, for the TCGA-BRCA, TCGA-NSCLC, and TCGA-CRC WSI-level bulk gene expression prediction tasks, the Pearson correlation increased by 14.36%, 9.27%, and 42.55%, respectively, compared to the average performance of two WSI-level single models. By leveraging multiple pathological foundation models using Meta-Encoder, it can further improve molecular characterization in pathology images to advance precision oncology.

bioinformatics↗

bioRxiv2025

Synergistic effects of APOE ϵ4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9{+/-}5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE {varepsilon}4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD. Significance StatementHippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimers disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.

neuroscience↗

bioRxiv2025

In silico model of basal ganglia Deep Brain Stimulation in Parkinsons Disease captures range of effective parameters for pathological beta power suppression

In Parkinsons disease (PD), the beta band ([12 30] Hz) component of basal ganglia activity is pathologically high. Deep brain stimulation (DBS) is an effective treatment to suppress symptoms of PD and is known to suppress pathological beta activity. However, the mechanism underlying this effect is not completely understood. Here, we tested the circuital effects of DBS in a computational model of the basal ganglia network in dopamine-depleted condition mimicking PD. Our model reproduces suppression of beta pathological oscillations in the basal ganglia network induced by subthalamic nucleus (STN) DBS. Crucially, this occurs for realistic levels of DBS intensity only if we incorporate short-term plasticity in STN projections to their downstream targets. STN stimulation hampers beta oscillations in the subthalamo-pallidal beta loop. This induces a progressive dephasing between this loop and the striato-pallidal beta loop, which leads in turn to a network-wide suppression of beta oscillations. This is also reflected in a restoration of the balance between D1 and D2 firing rates, which was altered by dopamine depletion. Moreover, the model also reproduces the DBS-induced gamma activity associated with symptom recovery. Finally, we explored the circuital effects of a broad range of DBS parameters in suppressing beta oscillations, focusing on the clinically relevant range of 60-150 Hz stimulation. The model suggests that 60-80 Hz stimulation frequencies might achieve beta desynchronization for an intensity even lower than the one needed at the standard 130 Hz frequency. Overall, our model lays the ground for in-silico tests of a broad spectrum of stimulation patterns. Author SummaryDeep brain stimulation (DBS) is an effective treatment for alleviating symptoms of Parkinsons disease (PD), but its underlying mechanism is unclear. Motor symptoms of PD are linked to exaggerated beta-band oscillations in a particular brain area called basal ganglia (BG). In this study, we developed a computational model to simulate how DBS affects brain circuits involved in PD. We found that stimulation can reduce pathological beta rhythms at realistic intensities only when we include realistic synaptic dynamics that temporarily adjust connection strength based on recent activity. Our model shows that stimulation decouples two available beta loops in the BG network and helps restore normal patterns of activity. Interestingly, we also found that stimulation at 60-80 Hz might be effective at lower intensities than the standard 130 Hz. Our work provides new insights into how DBS functions and supports safe and efficient exploration of a wide range of stimulation patterns.

bioengineering↗

bioRxiv2025

Parkinsons disease microglia induce endogenous alpha-Synuclein pathology in patient-specific midbrain organoids.

The accumulation of misfolded -synuclein and the loss of dopaminergic neurons are hallmarks of Parkinsons disease (PD), contributing to the development of synucleinopathies. Although considerable progress has been made in understanding -synucleins role in PD pathology, the precise mechanisms involved remain unclear. Human midbrain organoids (hMOs) have emerged as valuable models for studying PD, yet the lack of microglia limits the ability to investigate neuroimmune interactions. Recent studies show that integrating microglia into hMOs enhances neuronal maturation and functionality. Here, we generated a human midbrain assembloid model by incorporating iPSC-derived microglia into midbrain organoids from healthy control individuals and a PD patient carrying the SNCA triplication (3xSNCA) mutation. Our results show that 3xSNCA microglia alone are sufficient to induce early, endogenous formation of phosphorylated -synuclein (pS129) pathology in the absence of exogenous fibril seeding. This PD-pathology emerged as early as day 50 of culture and was not observed in models lacking microglia. These findings highlight a critical role for patient-derived microglia in driving - synuclein pathology and provide a physiologically relevant platform for studying early neuroimmune mechanisms in PD and testing potential therapeutic strategies.

neuroscience↗

bioRxiv2025

Characterizing a hallmark of glymphatic insufficiency: Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index and perivascular space

The glymphatic system is a recently elucidated waste clearance system in the brain, thought to be critical for the maintenance of homeostasis. Corpora amylacea or "wasteosomes", are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes have been proposed as a hallmark of glymphatic insufficiency predominantly due to: 1) their spatial localization around glymphatic drainage points including periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and, 2) their correlation with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs and are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimers disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular stenosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings suggest wasteosomes may serve as histological markers of impaired glymphatic drainage and provide new insights into the pathophysiology underlying white matter injury.

neuroscience↗

bioRxiv2025

Neurovascular Large artery dilatation increases the risk for Alzheimer's disease pathology

Alzheimers disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in AppNL-G-F mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001, respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in AppNL-G-F mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimers disease progression.

neuroscience↗

bioRxiv2025

Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce spread of pathology

Parkinsons Disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra due to Lewy body aggregates, primarily composed of misfolded alpha-synuclein (Syn). While PD progression is thought to be driven by a prion-like spread of Syn aggregates between neurons, the role of astrocytes remains unclear. Observations of Syn pathology in PD patient astrocytes suggest their potential involvement in processing aggregates. To investigate this, we studied astrocytes interactions with Syn pre-formed fibrils (PFFs) and their effects in astrocyte-neuron co-cultures on the spread of seed-competent Syn. Primary astrocytes quickly internalized and degraded Syn PFFs. However, degradation was significantly hindered by lysosome-compromising agents like chloroquine, Leupeptin, or CA-074. Adding astrocytes to neuron cultures reduced endogenous Syn aggregation, indicating their role in mitigating Syn pathology. When lysosome efficiency in astrocytes was compromised, their anti-seeding effect diminished. Moreover, lysosome-compromised astrocytes preloaded with Syn PFFs enhanced Syn pathology in neurons, whereas unimpaired astrocytes did not. These findings suggest astrocytes can modulate and contribute to Syn pathology spread, playing a significant role in PD pathogenesis.

neuroscience↗

bioRxiv2025

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimers disease (AD), yet its role in amyloid-{beta} (A{beta}) pathology remains unclear. Here, we show that PARP1 activation drives A{beta} pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric A{beta}1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered {gamma}-secretase complex composition, and enhanced A{beta} degradation via neprilysin. These findings position PARP1 as a critical mediator of A{beta} toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD. Significance StatementOur study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimers disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic A{beta}1-42 and mediates neuronal death, amyloid plaque formation, neuroinflammation, and cognitive deficits in a mouse model of AD. Importantly, genetic ablation of PARP1 not only protects neurons from A{beta} toxicity but also reduces amyloid burden by suppressing A{beta} production and enhancing its degradation. These findings highlight PARP1 as a critical regulator of amyloid pathology and neurodegeneration, and suggest that PARP1 inhibition may offer a promising therapeutic avenue for Alzheimers disease by simultaneously targeting multiple pathogenic mechanisms.

neuroscience↗

bioRxiv2025

N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer Disease

Neurodegenerative diseases like Alzheimers disease (AD) are characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein. Using a newly developed antibody specifically targeting this truncated variant, we demonstrate that this species accumulates early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments reveal that expression of this truncated Tau species exacerbates Tau pathology, whereas targeted immunotherapeutic with the specific antibody significantly reduces pathological Tau accumulation and prevents associated memory impairments. These findings position this newly identified Tau variant as both a marker of neurofibrillary degeneration and a pathogenic driver of neurodegeneration and supports its potential as a therapeutic target in Tau-related disorders, notably AD.

neuroscience↗

bioRxiv2025

A 'brain-first' mouse model of progressive alpha-synuclein pathology via intranasal rotenone administration

The precise aetiology of Parkinsons disease (PD) is still poorly understood, but it is thought to arise due to an intricate relationship between genes and the environment. Our study takes a unique approach to understanding the effect of environmental factors on the onset and progression of -synuclein (aSyn) pathology, a key feature of PD, from the olfactory bulb (OB) to other brain regions. In the present study, we evaluated the time-dependent progression of PD-like pathology by administering rotenone intranasally for 5.5 months in C57BL/6 male mice. We performed olfactory and motor tests and examined the aSyn accumulation, glial cell activation and dopaminergic neurodegeneration after 3, 4 and 5.5 months of rotenone exposure by immunoblotting and immunofluorescence techniques. We observed a time-dependent progression of aSyn accumulation from the OB to other brain regions, including the mid-brain and cortex. Consistently, we observed a time-dependent behavioural impairment, OB atrophy, progression of aSyn pathology, neuroinflammation and neurodegeneration. Our findings also established a link between distinct astrocyte activation and dopaminergic (DAergic) activity. In conclusion, this chronic and progressive mouse model mimics the brain-first type of progression of PD-like pathology in some PD patients, opening the possibility for testing potential disease-modifying interventions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/677764v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@5a983eorg.highwire.dtl.DTLVardef@1c115ceorg.highwire.dtl.DTLVardef@17eb778org.highwire.dtl.DTLVardef@3f3fa4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗