Biology subjects

Kulic, L.

Publications and source records attributed to Kulic, L..

4 recordsLinked to original sources

bioRxiv2026

Peripheral T-cell co-signalling states mark vulnerability and resilience to cerebral Aβ pathology

Adaptive immune responses may influence vulnerability and resilience in Alzheimers disease (AD), but relevant T-cell states remain unclear. We profiled peripheral immune cells by mass cytometry in 200 participants across distinct age groups, early AD and exceptional old age without dementia, relating immune features to amyloid-{beta} (A{beta}) PET, plasma biomarkers and longitudinal structural and cognitive outcomes. Inducible T-cell co-stimulator (ICOS) expression across CD4 and CD8 memory T-cells was associated with cerebral A{beta} pathology. In mild cognitive impairment (MCI), higher ICOS expression on CD8 memory T-cells strengthened the association between A{beta} load and hippocampal atrophy. A{beta}-derived peptides induced proliferative ICOS+CD25+ memory CD4 and CD8 T-cell responses predominantly in A{beta}-positive participants in an independent cohort. Conversely, higher programmed cell death protein 1 (PD-1) expression on CD8 effector-memory T-cells was associated with attenuated A{beta}-related episodic-memory decline in exceptionally old participants and was higher in stable MCI than in MCI-to-AD converters. These findings identify distinct co-stimulatory and co-inhibitory T-cell correlates of vulnerability and resilience.

immunology↗

bioRxiv2024

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer's disease

There is growing evidence that the adaptive immune system and neurodegenerative Alzheimers disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, in vitro T cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards {beta}- amyloid peptide and display an early enrichment of cytotoxic CD8+ effector/TEMRA cells in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI due to AD, we observed increased frequencies of CD8+ effector/TEMRA cells in the periphery, characterized by a pro-inflammatory gene expression profile and an overall decrease in antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial in the preclinical stage to promote specific CD4+ T cell responses, while in MCI it may be important to therapeutically target CD8+ T cell responses if these prove to be harmful.

immunology↗

bioRxiv2023

Early beta-amyloid accumulation in the brain is associated with peripheral T cell alterations

Fast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimers disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral {beta}-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for {beta}-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain {beta}-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help in the future to identify and develop novel diagnostic tools for early AD assessment and to better understand clinical outcomes.

immunology↗

bioRxiv2019

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

Brain calcification is associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of intracranial calcification in transgenic P301L mice overexpressing 4 repeat tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates were assessed using in vivo/ex vivo magnetic resonance imaging (MRI) with a gradient recalled echo sequence and micro computed tomography (CT). Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, {micro}CT detected hyperdense lesions. Occurrence of diamagnetic susceptibility lesions in the hippocampus, increased with age. Immunochemical staining of brain sections revealed bone protein-positive deposits. Furthermore, intra-neuronal and vessel-associated protein-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus. Protein-containing nodules were detected also in the thalamus in the absence of phosphorylated-tau deposition. In contrast, osteocalcin-containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated-tau. In summary, MRI and {micro}CT demonstrated imaging pattern of intracranial calcification, concomitant with immunohistochemical evidence of formation of protein deposits containing bone proteins along with phosphorylated-tau in the P301L mouse model of human tauopathy. The P301L mouse model may thus serve as a future model to study the pathogenesis of brain calcifications in tauopathies.

neuroscience↗