Biology subjects

Channappa, D.

Publications and source records attributed to Channappa, D..

7 recordsLinked to original sources

bioRxiv2026

An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain

N-glycosylation generates substantial molecular diversity, yet how glycan composition varies throughout aging remains poorly understood. We mapped the N-glycoproteome of brain, liver, spleen, kidney, and plasma across nine ages spanning the mouse lifespan, identifying 80,618 unique N-glycopeptides at 9,211 glycosites on 4,391 glycoproteins, together with matched proteomic trajectories (glycoproteinatlas.org). Organ identity was the dominant determinant of glycan composition, but numerous glycosites nevertheless underwent remodeling with age. The brain showed a prominent age-associated increase in short paucimannose glycans, driven in part by the age-associated increase in the glycan-processing enzyme HEXB. In white matter, a hotspot for this change, aging increased the paucimannosylation of Myelin oligodendrocyte glycoprotein (MOG), a major target of central nervous system autoimmunity. We identified MOG-reactive autoantibodies in aged individuals and patients with MOG antibody-associated disease (MOGAD) and showed that the glycan at MOG N60 modulates autoantibody binding. Experimental autoimmune encephalomyelitis (EAE) recapitulated a subset of the age-associated glycosite changes, revealing shared glycosylation signatures between aging and autoimmune targeting of MOG. Together, these findings reveal site-specific N-glycosylation as both a marker of age and a regulator of molecular interactions.

neuroscience↗

bioRxiv2026

Plasma proteomics reveals divergent sex-specific senescence and bone biology signatures across neurodegenerative diseases

Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimers disease(AD), Lewbody dementia(LB) and Parkinsons disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

neuroscience↗

bioRxiv2025

Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer's disease

The neurovascular unit is critical for brain health, and its dysfunction has been linked to Alzheimers disease (AD). However, a cell-type-resolved understanding of how diverse vascular cells become dysfunctional and contribute to disease has been missing. Here, we applied Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to build a comprehensive transcriptomic atlas from 101 individuals along AD progression. Our analysis of over 842,646 parenchymal and vascular nuclei reveals that vascular dysfunction in AD is driven by transcriptional changes rather than shifts in cell proportions, with brain endothelial cells (BECs) and smooth muscle cells (SMCs) most affected. Strikingly, these molecular signatures emerge early at the mild cognitive impairment (MCI) stage, implicating vascular dysfunction early in AD pathogenesis. Stratifying by pathology reveals distinct vascular responses to {beta}-amyloid and tau: {beta}-amyloid burden primarily perturbs BECs and SMCs, while tau pathology predominantly impacts glial cells. We identify dysregulated angiopoietin signaling across multiple vascular cell types as a key axis, with antagonistic ANGPT2 in vascular cells and ANGPT1 in astrocytes becoming progressively dysregulated with AD. Together, this work provides a foundational resource that reveals early and pathology-specific pathways of vascular dysfunction in AD. Key MessagesO_LIVINE-seq analysis from 101 individuals creates a comprehensive human brain vascular atlas across Alzheimers disease (AD) progression. C_LIO_LIAD vascular dysfunction is driven by transcriptional changes rather than shifts in cell proportions, with BECs and SMCs most affected. C_LIO_LITranscriptional signatures of vascular dysfunction emerge early at the mild cognitive impairment (MCI) stage, preceding severe cognitive symptoms and aligning more closely with AD than cognitively normal individuals. C_LIO_LIA{beta} and tau associate with distinct vascular changes: A{beta} mainly perturbs endothelial and smooth muscle cells, while tau impacts microglia and astrocytes. C_LIO_LIAngiopoietin signaling (antagonistic ANGPT2 in vascular cells vs. ANGPT1 in astrocytes) becomes progressively dysregulated during AD progression. C_LI

neuroscience↗

bioRxiv2024

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease

Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (A{beta}) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of A{beta} and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:A{beta}42, 10% beyond tau PET, and 50% beyond CSF NfL in A{beta} positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2- individuals (bottom 25th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by A{beta} and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of A{beta}, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

neuroscience↗

bioRxiv2024

Single-Cell Peripheral Immunoprofiling of Lewy Body Disease in a Multi-site Cohort

Studies implicated peripheral organs involvement in the development of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinsons Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). This study characterized peripheral immune responses unique to LBD at single-cell resolution. Peripheral mononuclear cell (PBMC) samples were collected from sites across the U.S. The diagnosis groups comprise healthy controls (HC, n=164), LBD (n=132), Alzheimers disease dementia (ADD, n=98), other neurodegenerative disease controls (NDC, n=21), and immune disease controls (IDC, n=14). PBMCs were activated with three stimulants, stained by surface and intracellular signal markers, and analyzed by flow cytometry, generating 1,184 immune features. Our model classified LBD from HC with an AUROC of 0.90{+/-}0.06. The same model distinguished LBD from ADD, NDC, IDC, or other common conditions associated with LBD. Model predictions were driven by pPLC{gamma}2, p38, and pSTAT5 signals from specific cell populations and activations.

neuroscience↗

bioRxiv2020

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity1-3. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans4--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

neuroscience↗

bioRxiv2019

CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by -synuclein accumulation that frequently associates with amyloid beta (A{beta}) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic A{beta} and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF A{beta} and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not A{beta}, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.\n\nOne sentence summaryCSF sTREM2 correlates with CSF tau in PD

neuroscience↗