Biology subjects

Spina, S.

Publications and source records attributed to Spina, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2026

Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD

Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.

neuroscience↗

bioRxiv2026

Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease

Frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Picks disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

neuroscience↗

bioRxiv2026

Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts

The standard approach to quantify amyloid (A{beta}) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of A{beta}-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant A{beta}-PET binding. In particular, A{beta}-PET positive participants who have posterior predominant binding are less likely to be APOE-{varepsilon}4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant A{beta} binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that A{beta}-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess A{beta}-PET is insufficient to capture meaningful signal from A{beta}-PET imaging. This work has implications for the diagnosis and treatment of Alzheimers disease and extends our understanding of the mechanisms governing variable A{beta}-PET distribution and its downstream effects.

neuroscience↗

bioRxiv2026

Tau-induced mitochondrial reverse electron transport drives neurodegeneration

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood1-6. Mitochondrial dysfunction is a common feature of tauopathies7,8. Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to taus physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

neuroscience↗

bioRxiv2026

Single-nucleus transcriptomics identifies a shared vulnerable excitatory neuronal population across typical and atypical Alzheimers disease

AO_SCPLOWBSTRACTC_SCPLOWAlzheimers disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimers disease.

neuroscience↗

bioRxiv2026

Distinct tau filament folds in familial frontotemporal dementia due to the MAPT S305I mutation

Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often cause severe, early-onset disease with pathology that is distinct yet partially overlapping with sporadic cases. Here, we evaluated post-mortem tissue from a patient with FTLD-tau due to MAPT S305I showing neuropathology most consistent with argyrophilic grain disease (AGD), a prevalent limbic tauopathy of aging. Structures determined by cryo-electron microscopy reveal tau filament folds that differ from those found in sporadic AGD or other tauopathies and feature a 4-layer architecture stabilized by the Ile substitution within its core. Comparative structural analysis reveals conserved motifs are shared among AGD, corticobasal degeneration, and MAPT P301T. A well-defined density stacks along a cationic cleft, indicative of a bound RNA-like polyanion or small-molecule. In vitro analysis shows the S305I mutation promotes fibrilization relative to normal tau. These results demonstrate that MAPT S305I stabilizes a distinct aggregation-prone tau fold that likely contributes to disease pathology and heterogeneity beyond its known splicing defects, and underscore potential limitations of using the most pathologically similar genetic form as a model for sporadic FTLD-tau.

neuroscience↗

bioRxiv2026

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglia (iMG) into progranulin (Grn)-deficient mice. We find that wild-type, but not Grn-deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders. One Sentence SummaryOur study demonstrates that xenotransplantation of wild-type human iPSC-derived microglia into progranulin-deficient mice mitigates core neuropathological, network-level, and behavioral features of Frontotemporal Dementia.

neuroscience↗

bioRxiv2025

TAF15 amyloids propagate via defined motifs in a prion-like fashion

TATA-box binding protein-associated factor 15 (TAF15) is an RNA-binding member of the FET family recently identified as the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD-FET) cases. Although TAF15 is also linked to amyotrophic lateral sclerosis (ALS), the molecular basis and propagation behavior of its aggregates remain unknown. In this work, we show that recombinant TAF15 forms amyloid fibrils under physiological conditions and developed a single-fluorophore TAF15 biosensor to quantitatively monitor their cellular propagation. Using this system, we demonstrate that both recombinant TAF15 fibrils and pathological aggregates extracted from atypical FTLD with ubiquitin inclusions (aFTLD-U) patient brains seed aggregation efficiently and transmit serially between cells, demonstrating hallmark features of prion-like propagation. Seeding was specific to TAF15 and absent for other amyloidogenic proteins, including the homologous protein fused-in-sarcoma (FUS), revealing an unexpected cross-seeding barrier. Occasional colocalization of FUS within TAF15 inclusions was observed upon transient co-expression, suggesting that FUS can be passively recruited rather than acting as an inducer of pathology in FTLD-FET brains. Computational and peptide-based experimental mapping identified multiple aggregation-prone regions within the TAF15 low-complexity domain that coincide with hotspots stabilizing the core of ex vivo TAF15 amyloid fibrils. These short motifs encode the propagation propensity of TAF15 aggregation in vitro and in cells. Together, these findings establish TAF15 as a bona fide amyloid-forming, prion-like protein and define the sequence grammar underlying its self-assembly, providing a mechanistic framework for its role in FTLD-FET and ALS and offering tractable molecular targets for therapeutic intervention.

biophysics↗

bioRxiv2025

Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis

Activity-dependent modulation of synaptic strength is critical for encoding memories and it is inhibited in tauopathies including Alzheimers disease (AD) and Frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Pathogenic tau accumulates in neurons where it obstructs synaptic plasticity. How tau blocks synaptic plasticity leading to memory loss is unclear. Here, we show that FTLD-tau inhibits plasticity by blocking activity-dependent protein synthesis in dendrites. In the plasticity-associated translatome, we identified a subset of downregulated translated mRNAs in FTLD-tau neurons that encode postsynaptic plasticity regulators. Protein synthesis was blocked by FTLD-tau binding to eIF4B which caused eIF4B dissociation from the translation initiation complex and reduced dendritic eIF4B levels. Inhibiting the tau-eIF4B interaction or enhancing eIF4B levels in FTLD-tau neurons restored local protein synthesis and synaptic plasticity. Together, this suggests that pathogenic tau binding to eIF4B disables the local synthesis of plasticity-related proteins that drive synapse strengthening and memory formation.

neuroscience↗

bioRxiv2025

Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states

The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimers disease (AD), Picks disease (PiD), and progressive supranuclear palsy (PSP). Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across AD, PiD, and PSP, we define cell-type-specific cis-regulatory elements (CREs) across six cell types and fifty subclasses. Comparing disease-dynamic CREs across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in PiD. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, introducing modifiable pathways governing resilience for therapeutic consideration.

genomics↗

bioRxiv2025

Tau-Associated Neuronal Loss in the Intermediate Nucleus of the Human Hypothalamus (VLPO Analog): Unveiling the Basis of NREM Sleep Dysfunction in PSP and Alzheimer's Disease

Sleep disturbances are prevalent in Alzheimers disease (AD) and Progressive Supranuclear Palsy (PSP), often exacerbating disease progression. Understanding the neuropathological basis of these disturbances is essential for identifying potential therapeutic targets. This study investigates the intermediate nucleus (IntN) of the human hypothalamus--a key sleep-regulating region analogous to the rodent ventrolateral preoptic area (VLPO)--to assess neuronal loss and tau pathology in AD and PSP. Using postmortem brain tissue, we applied unbiased stereology to quantify galanin-expressing neurons and phosphorylated tau (p-tau) accumulation. Among 26 cases analyzed, both AD and PSP exhibited significant neuronal loss in the IntN, with PSP showing the most pronounced reduction (84.9% fewer neurons than healthy controls [HC]). In AD, neuronal loss correlated with Braak staging, with late-stage AD cases (Braak 5-6) demonstrating a 76.9% reduction in galanin-expressing neurons compared to HC, while non-galanin neurons exhibited a more moderate decline (45.7%). In PSP, extensive neuronal loss precluded a clear assessment of p-tau burden. These findings suggest a differential neuronal vulnerability to tau pathology across diseases, aligning with distinct sleep disturbances observed in each condition. PSP, characterized by severe insomnia despite preserved wake-promoting neurons, may be explained by the near-total loss of NREM sleep-regulating neurons. In contrast, AD exhibits a progressive decline in both wake- and sleep-promoting neurons, contributing to excessive daytime sleepiness and sleep fragmentation. This study provides critical insights into the selective neuronal vulnerabilities underlying sleep dysfunction in tauopathies, emphasizing the need for targeted interventions to mitigate sleep disturbances in these disorders.

neuroscience↗

bioRxiv2025

β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity

To elucidate the impact of A{beta} pathology on microglia in Alzheimers disease pathogenesis, we profiled the microglia surfaceome following treatment with A{beta} fibrils. Our findings reveal that A{beta}-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating that glial GPC4 contributes to a toxic cellular program during neurodegeneration. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. These studies offer a mechanistic framework linking A{beta} and tau pathology through microglial HSPGs and APOE.

neuroscience↗

bioRxiv2024

Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer's disease

Germline genetic architecture of Alzheimers disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms that enable microglia to mediate protective responses to AD pathology remain elusive. Adgrg1 is specifically expressed in yolk-sac-derived microglia. This study reveals the role of yolk-sac-derived microglia in AD pathology, highlighting the function of ADGRG1 in modulating microglial protective responses to amyloid deposition. Utilizing both constitutive and inducible microglial Adgrg1 knockout 5xFAD models, we demonstrate that Adgrg1 deficiency leads to increased amyloid deposition, exacerbated neuropathology, and accelerated cognitive impairment. Transcriptomic analyses reveal a distinct microglial state characterized by downregulated genes associated with homeostasis, phagocytosis, and lysosomal functions. Functional assays in mouse models and human embryonic stem cells-derived microglia support that microglial ADGRG1 is required for efficient A{beta} phagocytosis. Together, these results uncover a GPCR-dependent microglial response to A{beta}, pointing towards potential therapeutic strategies to alleviate disease progression by enhancing microglial functional competence.

neuroscience↗

bioRxiv2024

Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy

BackgroundExposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimers disease (AD), including a subset characterized neuropathologically at autopsy. MethodsProximity extension assay (Olink Explore(R)) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N=16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE+ (N=7) and CTE-(N=9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. ResultsDifferential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. ConclusionsMolecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.

molecular biology↗

bioRxiv2024

The wake and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimers disease

BackgroundSleep-wake dysfunction is an early and common event in Alzheimers disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxN and MCHN loss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD. MethodsPostmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter(R) (Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05. ResultsWe observed a progressive decline in OrxN alongside a relative preservation of MCHN. OrxN decreased by 58% (p=.03) by Braak stages (BB) 1-2 and further declined to 81% (p=.03) by BB 5-6. Conversely, MCHN demonstrated a non-statistical significant decline (27%, p=.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxN loss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched. ConclusionsTo date, OrxN loss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxN correlates with specific neuroinflammation, glial profile changes, and overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxN loss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.

neuroscience↗

bioRxiv2024

Spatially conserved pathoprotein profiling in the human suprachiasmatic nucleus in progressive Alzheimer disease stages

Individuals with Alzheimers Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak stage 0) and 36 subjects at progressive Braak stages (I, II, and VI). To investigate potential AD-specific changes, we measured the neuronal counts of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) positive neurons, along with the Braak stages in the SCN. We investigated in adjacent hypothalamic nuclei which are also composed of AVP+ neurons but show more resilience to AD: paraventricular nucleus (PVN) and supraoptic nucleus (SON). To understand the dysregulated proteins associated to AD progression, we performed in-situ proteomics, investigating 57 proteins, including commonly dysregulated in AD, using GeoMx Digital Spatial Profiling (DSP) in the three nuclei (total of 703 area of interests). Neurofibrillary tangles (NFTs) and tau fibrils were found selectively in SCN. We failed to detect NFTs in SON, only a mild dysregulation of p-tau at Braak VI in PVN and SON. Amyloid plaque was absent in the SCN and SON. Additionally, the SCN showed increased glial proteins already at Braak stage I, whereas the level of these proteins sustained in the other nuclei. The SCN is exclusively vulnerable to AD-tau pathology and show immune dysregulation even at Braak I but is protected against amyloid plaque. This finding revealed selectively in amnestic AD, showing more resilience in AD variant. This tau-related molecular dysregulation in the SCN contributes to circadian rhythm disturbances in AD, a phenomenon observed before the onset of cognitive disorder.

neuroscience↗

bioRxiv2023

Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cellgenomics

Summary/AbstractThe development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease-specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.

neuroscience↗