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Results for “pathology”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2020

Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

Tau pathology is a diagnostic feature of Alzheimers disease (AD) but is also a prominent feature of Parkinsons disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathologys initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

neuroscience↗

bioRxiv2023

Machine Learning Classification of Alzheimer's Disease Pathology Reveals Diffuse Amyloid as a Major Predictor of Cognitive Impairment in Human Hippocampal Subregions

Analyzing Alzheimers disease (AD) pathology within anatomical subregions is a significant challenge, often carried out by pathologists using a standardized, semi-quantitative approach. To augment traditional methods, a high-throughput, high-resolution pipeline was created to classify the distribution of AD pathology within hippocampal subregions. USC ADRC post-mortem tissue sections from 51 patients were stained with 4G8 for amyloid, Gallyas for neurofibrillary tangles (NFTs) and Iba1 for microglia. Machine learning (ML) techniques were utilized to identify and classify amyloid pathology (dense, diffuse and APP (amyloid precursor protein)), NFTs, neuritic plaques and microglia. These classifications were overlaid within manually segmented regions (aligned with the Allen Human Brain Atlas) to create detailed pathology maps. Cases were separated into low, intermediate, or high AD stages. Further data extraction enabled quantification of plaque size and pathology density alongside ApoE genotype, sex, and cognitive status. Our findings revealed that the increase in pathology burden across AD stages was driven mainly by diffuse amyloid. The pre and para-subiculum had the highest levels of diffuse amyloid while NFTs were highest in the A36 region in high AD cases. Moreover, different pathology types had distinct trajectories across disease stages. In a subset of AD cases, microglia were elevated in intermediate and high compared to low AD. Microglia also correlated with amyloid pathology in the Dentate Gyrus. The size of dense plaques, which may represent microglial function, was lower in ApoE4 carriers. In addition, individuals with memory impairment had higher levels of both dense and diffuse amyloid. Taken together, our findings integrating ML classification approaches with anatomical segmentation maps provide new insights on the complexity of disease pathology in AD progression. Specifically, we identified diffuse amyloid pathology as being a major driver of AD in our cohort, regions of interest and microglial responses that might advance AD diagnosis and treatment.

neuroscience↗

bioRxiv2024

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau

BackgroundPathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing -synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimers disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both -synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between -synuclein, tau, and granulovacuolar degeneration. MethodsWe developed a mouse model of limbic-predominant -synucleinopathy by stereotactic injection of -synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of -synuclein pathology with tau and GVB formation. ResultsOur model displayed widespread -synuclein pathology with a limbic predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of -synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1{delta}-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF-injection, suggesting that pathological -synuclein alone is sufficient to elicit GVB formation. ConclusionsOur findings support that -synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of -synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.

neuroscience↗

bioRxiv2025

Molecular Subtyping Based on Hippocampal Cryptic Exon Burden Reveals Proteome-wide Changes Associated with TDP-43 Pathology across the Spectrum of LATE and Alzheimer's Disease

TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimers disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, {beta}-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies ({beta}-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7. While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of {beta}-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, {beta}-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease

neuroscience↗

bioRxiv2020

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Increasing evidence suggests that crosstalk between -synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinsons disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinsons disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology. Therefore, we sought to test the hypothesis that early -synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala. We combined a model of intracerebral -synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinsons disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as -synuclein pathology in male mice. Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of -synuclein preformed fibrils into the striatum resulted in pronounced -synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions. Our results suggest that early stage -synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model. Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinsons disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of -synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

neuroscience↗

bioRxiv2021

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

Pathologic -synuclein (-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid {beta} precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by -syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of -syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by -syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for -syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic -syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinsons disease and related -synucleinopathies. One Sentence SummaryAplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -synuclein. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/442157v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1d746bforg.highwire.dtl.DTLVardef@65acb2org.highwire.dtl.DTLVardef@12cf2f0org.highwire.dtl.DTLVardef@19d6e_HPS_FORMAT_FIGEXP M_FIG Aplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic -synuclein. Aplp1 is a receptor that drives pathologic -syn transmission, and genetic depletion of Aplp1 can significantly reduce the -synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic -syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic -syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks -syn PFF-induced neurodegeneration. C_FIG

neuroscience↗

bioRxiv2023

Hippocampal subfield vulnerability to α-synuclein pathology precedes neurodegeneration and cognitive dysfunction

Cognitive dysfunction is a salient feature of Parkinsons disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of -synuclein fibrils in vivo, we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of -synuclein fibrils within the mouse forebrain, we measured the burden of -synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to - synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of -synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with -synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of -synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction. HighlightsO_LIMice injected with -synuclein fibrils develop hippocampal and cortical - synuclein pathology with a dynamic regional burden at 1-, 3-, and 6-months post-injection. C_LIO_LISilver-positive neuronal processes are an early and enduring degenerative feature of the fibril model, while extensive neurodegeneration of the hippocampal CA2/3 subfield is detected at 6-months post-injection. C_LIO_LIMice exhibit progressive hippocampal-dependent spatial learning and memory deficits. C_LIO_LIForebrain injection of -synuclein fibrils may be used to model aspects of Lewy-related cognitive dysfunction. C_LI

neuroscience↗

bioRxiv2023

Neuronal Tau Pathology Worsens Late Phase White Matter Degeneration After Traumatic Brain Injury in Transgenic Mice

Traumatic brain injury (TBI) causes diffuse axonal injury which can produce chronic white matter pathology and subsequent post-traumatic neurodegeneration with poor patient outcomes. Tau modulates axon cytoskeletal functions and undergoes phosphorylation and mis-localization in neurodegenerative disorders. The effects of tau pathology on neurodegeneration after TBI are unclear. We used mice with neuronal expression of human mutant tau to examine effects of pathological tau on white matter pathology after TBI. Adult male and female hTau.P301S (Tg2541) transgenic and wild type (Wt) mice received either moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily x 5), or matched sham procedures. Acutely, s-TBI produced more extensive axon damage in the corpus callosum (CC) as compared to r-mTBI. After s-TBI, significant CC thinning was present at 6 weeks and 4 months post-injury in Wt and transgenic mice, with homozygous tau expression producing additional pathology of late demyelination. In contrast, r-mTBI did not produce significant CC thinning except at the chronic time point of 4 months in homozygous mice, which exhibited significant CC atrophy (-29.7%) with increased CC microgliosis, but not astrogliosis. Serum biomarker quantification demonstrated neurofilament light detection of early axonal damage one day post-injury in Wt and homozygous mice. At 4 months, high tau and neurofilament in homozygous mice implicated tau in chronic axon pathology. Conclusions: Neuronal tau pathology differentially exacerbated CC pathology based on injury severity and chronicity. Ongoing CC atrophy from s-TBI became accompanied by late demyelination. Pathological tau significantly worsened CC atrophy during the chronic phase after r-mTBI.

neuroscience↗

bioRxiv2023

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies.

BackgroundAbnormal aggregation of tau protein that leads to brain inclusions is a common feature of neurodegenerative disorders called tauopathies. Recent evidence suggests the involvement of lipid metabolic deregulations in the pathogenesis of tauopathies. However, the role of tau protein in the regulation of lipid metabolism is much less characterized and not well understood. MethodsWe used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N-and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. ResultsWe showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. The results showed that dysregulation of lipid composition by pathological tau leads to disruption of the microenvironment and further propagation of pathology. ConclusionOur results revealed that lipid metabolism is significantly affected during different stages of tau pathology and provide new evidence that supports the contribution of pathological tau proteins in individual lipid pathways. Our data suggests that biologically active membrane lipids such as phospholipids and sphingolipids could represent new potential next-generation therapeutic targets in tauopathies.

neuroscience↗

bioRxiv2024

MOTOR MODULES ARE LARGELY UNAFFECTED BY PATHOLOGICAL WALKING BIOMECHANICS: A SIMULATION STUDY

BackgroundMotor module (a.k.a. muscle synergy) analysis has frequently been used to provide insight into changes in muscle coordination associated with declines in walking performance, to evaluate the effect of different rehabilitation intervention, and more recently, to control exoskeletons and prosthetic devices. However, it remains unclear whether changes in muscle coordination revealed via motor module analysis stem from pathological walking biomechanics or pathological neural control. This distinction has important implications for the use of motor module analysis for rehabilitation interventions and device design. Thus, this study aims to elucidate the extent to which motor modules emerge from pathological walking biomechanics. MethodsWe conducted a series of computer simulations using OpenSim Moco to simulate abnormal biomechanics by manipulating speed, asymmetry, and step width in a three-dimensional musculoskeletal model. We extracted motor modules using nonnegative matrix factorization from the muscle activation from each simulation. We then examined how alterations in walking biomechanics influenced the number and structure of extracted motor modules and compared the findings to previous experimental studies. ResultsThe motor modules identified from our simulations were similar to those identified from previously published experiments of non-pathological walking. Moreover, our findings indicate that the same motor modules can be used to generate a range of pathological-like waking biomechanics by modulating their recruit timing over the gait cycle. These results contrast with experimental studies in which pathological-like walking biomechanics are accompanied by a reduction in motor module number and alterations in their structure. ConclusionsThis study highlights that pathological walking biomechanics do not necessarily require pathological motor modules. In other words, changes in number and structure of motor modules can be a valuable indicator of alterations in neuromuscular control and may therefore be useful for guiding rehabilitation interventions and controlling exoskeletons and prosthetic devices in individuals with pathological walking function.

bioengineering↗

bioRxiv2024

MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity

Lewy pathology, consisting of Lewy bodies and Lewy neurites, is the pathological hallmark of synucle-inopathies such as Parkinsons disease and dementia with Lewy bodies, but it is generally thought to represent late-stage pathological changes. In contrast, -synuclein oligomers are regarded as early-stage pathology, likely involved in disease progression and cellular toxicity. Oligomers, however, are not de-tected by standard immunohistochemistry but require specific detection techniques such as the proxim-ity ligation assay (PLA). Here, we describe the MJF-14 PLA, a new PLA towards aggregated -synuclein with unprecedented specificity, attained by the utilization of aggregate conformation-specific -synu-clein antibody MJFR-14-6-4-2 (hereafter MJF-14). Signal in the assay directly correlates with -synuclein aggregation in SH-SY5Y cells, as treatment with aggregation inhibitor ASI1D significantly lowers PLA sig-nal. In human cortical neurons, MJF-14 PLA detects pre-formed fibril-induced aggregation, especially prominent when using stealth PFFs invisible to the MJF-14 antibody. Co-labelling of MJF-14 PLA and pS129--synuclein immunofluorescence in post-mortem dementia with Lewy bodies cases showed that while the MJF-14 PLA reveals extensive non-inclusion pathology, it is not sensitive towards Lewy bodies. In Parkinsons disease brain, direct comparison of PLA and IHC with the MJF-14 antibody, combined with machine learning-based quantification, showed striking -synuclein pathology preceding the formation of conventional Lewy pathology. The majority of the PLA-revealed non-inclusion pathology was found in the neuropil, including some clearly located in the presynaptic terminals. With this work, we introduce an improved -synuclein aggregate PLA to uncover abundant non-inclusion pathology, which deserves future validation with multiple brain bank resources and in different synucleinopathies.

neuroscience↗

bioRxiv2024

Caveolin-1 and Aquaporin-4 as Mediators of Fibrinogen-Driven Cerebrovascular Pathology in Hereditary Cerebral Amyloid Angiopathy

Cerebral Amyloid Angiopathy (CAA), characterized by amyloid-{beta} (A{beta}) accumulation within perivascular spaces (PVS), contributes to vascular damage and inflammation in Alzheimers disease (AD). Despite its significance, the mechanisms driving A{beta} deposition in PVS and the resulting vascular pathology remain poorly understood. Growing evidence suggests that fibrinogen, the main component in blood clots, interacts with A{beta} and exacerbates inflammation in AD. Fibrinogen also co-deposits with A{beta} in the PVS of CAA-positive vessels in the brains of hereditary CAA patients. However, the mechanisms by which fibrinogen contributes to cerebrovascular impairment remain poorly understood. To investigate this, we used TgSwDI transgenic mice, which develop robust CAA pathology, and observed a significant increase in fibrin(ogen) extravasation and colocalization with A{beta} in the PVS. Moreover, we observed a significant aquaporin-4 (AQP4) depolarization in CAA-laden blood vessels of TgSwDI mice, which correlated with fibrin(ogen)-A{beta} colocalization. Given AQP4 crucial role in A{beta} clearance through glymphatic pathway, its depolarization may disrupt critical A{beta} clearance, thereby exacerbating CAA pathology. Additionally, Caveolin-1, a protein involved in non-specific transcytosis across the endothelium, significantly increased with age in TgSwDI mice and correlated with fibrin(ogen) extravasation. To further explore the relationship between fibrin(ogen) and these cerebrovascular alterations, we depleted fibrinogen in TgSwDI mice using siRNA approach. This intervention resulted in decreased CAA, restored polarized expression of AQP4, reduced caveolin-1 levels, attenuated microglial activation, and improved spatial memory in fibrinogen-depleted TgSwDI mice. These findings suggest that targeting fibrinogen could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology. Significance StatementOur study uncovers the mechanism by which fibrin(ogen)-A{beta} colocalization exacerbates CAA pathology. Our findings highlight the potential link between fibrinogen/ fibrin(ogen)-A{beta} colocalization and AQP4 depolarization thereby exacerbating CAA pathology. The age-dependent increase of endothelial caveolin-1 could facilitate fibrin(ogen) extravasation, assisting the later to binds to A{beta} in the perivascular space which ultimately induce microglial neuroinflammation and AQP4 depolarization, thus exacerbating CAA pathology. Furthermore, fibrinogen depletion could mitigate CAA severity, reduce microglial activation, restore AQP4 polarization and memory impairment. These results suggest that targeting fibrinogen and caveolin-1-mediated transcytosis may offer new strategies to address CAA-associated cerebrovascular pathology.

neuroscience↗

bioRxiv2025

Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy Body Dementia

Posterior cortical impairments in visuospatial/perceptual function are common non-motor symptoms of the Lewy Body Dementias (LBD) and are relatively specific for LBDs compared to other dementias. Across populations, cognitive impairments correlate with the presence of -synuclein (-syn) pathology in limbic and neocortical brain regions. However, the specific role that -syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing -syn pathology in primary visual cortex (V1) in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this, we injected -syn pre-formed fibrils (PFF) into V1, causing the formation of sparse Lewy-like pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified -syn pathology using C05-05, a fluorescent ligand that binds aggregated -syn. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4-5 months post-injection (MPI). Neurons with somatic Lewy-like inclusions showed reduced activity compared to neighboring neurons without inclusions. Conversely, neurons without somatic inclusions showed increased activity, positively correlated with the local burden of -syn pathology. Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that -syn pathology leads to reductions in neuronal activity in cells with somatic inclusions and reciprocal changes in local population activity but does not impair visuoperceptual function. Reflecting the early stages of neocortical -syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and -syn pathology across patients.

neuroscience↗

bioRxiv2025

The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies

Apolipoprotein E (APOE) genotype is well known to influence both amyloid-{beta} (A{beta}) and tau pathologies and risk for Alzheimers disease (AD), but it also affects -synuclein (-syn) levels, Lewy pathology and risk of dementia in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on -syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on A{beta}, tau and -syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-Syn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including A{beta}, tau, A{beta}-induced tau after paired helical filament (PHF)-tau intracortical injections, and -syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased A{beta}-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change A{beta}-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although A{beta} levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical -syn PFF injection and reduced formation in spinal cord after -syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including A{beta} plaque, tau and -syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/686857v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1104377org.highwire.dtl.DTLVardef@bd6c70org.highwire.dtl.DTLVardef@1a4e44org.highwire.dtl.DTLVardef@1087d7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Patient-derived tau-seeded human neuronal chimeras recapitulate mature Alzheimer's tau pathology and uncover human-specific neuronal vulnerability

Tau pathology is a central hallmark of Alzheimers disease (AD) and strongly correlates with cognitive decline, yet the development of tau-targeted therapies has been hindered by the inability of existing models to capture human-specific disease features, particularly the mature forms of AD tau pathology. Moreover, species-specific mechanisms underlying tau pathology remain poorly understood. Here, we establish a patient-derived tau-seeded human neuronal chimera model by transplanting human pluripotent stem cell (hPSC)-derived neural progenitor cells into neonatal mouse brains, followed by intracerebral injection of pathological tau seeds from postmortem AD brains. Human neurons matured in vivo and recapitulated adult human tau features, including all six isoforms with an approximately 1:1 3R:4R ratio. Upon seeding, aged human neurons without FTD mutations faithfully developed robust, mature AD tau pathology, including neurofibrillary tangles (NFTs) and neuropil threads composed of paired helical filaments (PHFs) and straight filaments (SFs) containing 3R and 4R tau, closely mirroring advanced-stage AD. This pathology accumulated and spread across anatomically connected regions, accompanied by neurodegeneration, elevated plasma pTau-217, and memory deficits. Strikingly, tau pathology was largely restricted to human neurons, revealing a pronounced human-specific vulnerability. Mechanistically, snRNA-seq showed that human neurons exhibited higher basal expression of tau-uptake genes and widespread synaptic suppression following tau exposure, whereas mouse neurons remained transcriptomically resilient. Finally, the familial AD mutation PSEN2 N141I exacerbated tau pathology and synaptic loss in human neurons. Together, this model recapitulates the molecular, structural, and functional hallmarks of mature AD tau pathology in human neurons in vivo and reveals intrinsic, species-specific vulnerability, providing a human-relevant in vivo platform for mechanistic studies and therapeutic development.

neuroscience↗

bioRxiv2020

Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy

In the early stages of Alzheimers disease (AD), tau pathology first develops in the entorhinal cortex (EC), then spreads to the hippocampus and at later stages, to the neocortex. Pathology in the neocortex correlates with impaired cognitive performance. Overall, tau pathology correlates well with neurodegeneration but the spatial and temporal association between tau pathology and overt volume loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) we mapped the spatio-temporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, co-registered in vivo MRI atlas identified particular regions in the medial temporal lobe (MTL) that had significant volume reduction. The medial entorhinal cortex (MEC) and pre-/para-subiculum (PPS) had the most significant atrophy at the early stage, but atrophy then spread into the hippocampus, most notably, the CA1, dentate gyrus (DG) and subiculum (Sub). TBM-related atrophy in the DG and Sub preceded overt cell loss that has been reported in ex vivo studies in the same mouse model. By unifying an ex vivo 3D reconstruction of tau pathology with the TBM-MRI results we mapped the progression of atrophy in the MTL with the corresponding spread of tau pathology. Our study shows that there is an association between the spread of tau pathology and TBM-related atrophy from the EC to the hippocampus, but atrophy in the DG and Sub preceded overt cell loss. One Sentence SummarySpread of tau pathology in a mouse model of Alzheimers disease assessed by MRI was associated with reduced brain tissue volume but not neuronal loss.

neuroscience↗

bioRxiv2020

Neuroinflammation characterizes the earliest changes in Alzheimer's disease pathology and associated subjective cognitive impairment in adult hydrocephalus biopsies

In an effort to better characterize the transcriptomic changes that accompany early Alzheimers disease (AD) pathology in living patients and correlate with contemporaneous cognitive data, we performed RNA-seq on 106 cortical biopsies that were taken during shunt placement for adult onset hydrocephalus with varying degrees of comorbid AD pathology. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of {beta}-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Interestingly, downregulation of homeostatic genes and upregulation of disease-associated genes also correlate with microglial plaque invasion and an activated microglial morphology, and this change is not sensitive to cognitive status, suggesting that an initial microglial response to AD pathology is eventually maladaptive. Taken together, these findings highlight a restricted set of microglial and non-microglial genes and suggest that early AD pathology is largely characterized by a loss of homeostatic genes and an activated microglial phenotype that continues to evolve in conjunction with accumulating AD pathology in the setting of subjective cognitive decline.

neuroscience↗

bioRxiv2022

Concomitant AD and DLB pathologies shape subfield microglia responses in the hippocampus

Hippocampal alteration is at the centre of memory decline in the most common age-related neurodegenerative diseases: Alzheimers disease (AD) and Dementia with Lewy Bodies (DLB). However, the subregional deterioration of the hippocampus differs between both diseases with more severe atrophy in the CA1 subfield of the AD patients. How AD and DLB-typical pathologies compose the various local microenvironment of the hippocampus across AD and DLB needs to be further explored to understand this process. Additionally, microglia responses could further impact the atrophy rate. Some studies suggest that microglia react differently according to the underlying neurodegenerative disorder. How microglia are transformed across hippocampal subfields in AD and DLB, and how their changes are associated with disease-typical pathologies remains to be determined. To these purposes, we performed a volumetric analysis of phospho-Tau (P-Tau), Amyloid-{beta} (A{beta}), and phospho--Synuclein (P-Syn) loads, quantified and classified microglia according to distinct morphological phenotypes using high-resolution confocal 3D microscopy of hippocampal CA1, CA3 and DG/CA4 subfields of late-onset AD (n=10) and DLB (n=8) as well as age-matched control samples (n=11). We found that each of the Tau, A{beta} and Synuclein pathologies followed a specific subregional distribution, relatively preserved across AD and DLB. P-Tau, A{beta} and P-Syn burdens were significantly exacerbated in AD, with Tau pathology being particularly severe in the AD CA1. P-Tau and P-Syn burdens were highly correlated across subfields and conditions (R2Spear = 0.79; P < 0.001) and result from a local co-distribution of P-Tau and P-Syn inclusions in neighbouring neurons, with only a low proportion of double-positive cells. In parallel, we assessed the changes of the microglia responses by measuring 16 morphological features of more than 35,000 individual microglial cells and classifying them into seven-distinct morphological clusters. We found microglia features- and clusters-variations subfield- and condition-dependent. Two of the seven morphological clusters, with more amoeboid and less branched forms, were identified as disease-enriched and found to be further increased in AD. Interestingly, some microglial features or clusters were associated with one but more often with a combination of two pathologies in a subfield-dependent manner. In conclusion, our study shows a multimodal association of the hippocampal microglia responses with the co-occurrence, distribution and severity of AD and DLB pathologies. In DLB hippocampi, pathological imprint and microglia responses follow AD trends but with lesser severity. Our study suggests that the increased pathological burdens of P-Tau and P-Syn and associated microglia alterations are involved in a more severe deterioration of the CA1 in AD as compared to DLB.

neuroscience↗