Biology subjects

Croese, T.

Publications and source records attributed to Croese, T..

4 recordsLinked to original sources

bioRxiv2026

Disruption of the Brain-Spleen Axis Impairs Monocyte-Microglia Communication and Accelerates Disease Progression in a Model of Amyloidosis

Alzheimers disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis revealed reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in coping with disease, we denervated the splenic nerve at an early presymptomatic stage. This intervention accelerated cognitive decline, impaired splenic hematopoiesis, diminished monocyte recruitment to the brain, disrupted monocyte-microglia signaling networks, and reduced the transition of microglia from a homeostatic to the disease-associated (DAM) state. Conversely, enhancing splenic noradrenergic input increased hematopoiesis, restored monocyte homing to the brain, and delayed cognitive impairment. The protective role of splenic monocytes was independently validated in a retinal cytotoxic injury model, in which splenic denervation impaired post-insult retinal ganglion cell survival. Together, these findings identify an active brain-spleen circuit in regulating monocyte recruitment and establish peripheral monocytes as key drivers of microglial state transitions and disease progression.

neuroscience↗

bioRxiv2025

Systemic administration of PD-L1 blocking antibodies leads to removal of senescent microglia

Senescent microglia develop during aging and Alzheimers disease (AD), driving chronic neuroinflammation. Here we hypothesized that the previously observed disease-modifying effects of PD-1/PD-L1 blockade occur through clearance of senescent microglia. Using CyTOF, we found that a single systemic anti-PD-L1 injection leads to rapid elimination of senescent microglia in 5xFAD and aged wild-type mice, independently of Fc effector function, while increasing homeostatic microglia. These findings suggest that immune rejuvenation via PD-L1 blockade promotes disease modification in AD through senescent-microglial elimination.

neuroscience↗

bioRxiv2023

TREM2-dependent senescent microglia conserved in aging and Alzheimer's disease

Dementia in general, and Alzheimers disease (AD) in particular, are age-related diseases1,2. AD is associated with multiple causative factors3,4, among which local brain inflammation plays a significant role5. Microglia, the brain-resident immune cells6,7, are activated along the disease course7. Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor8,9. A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

neuroscience↗

bioRxiv2022

Accelerated cognitive decline in obese mouse model of Alzheimer's disease is linked to sialic acid-driven immune deregulation

Systemic immunity supports healthy brain homeostasis. Accordingly, conditions causing systemic immune deregulation may accelerate onset of neurodegeneration in predisposed individuals. Here we show that, in the 5xFAD mouse model of Alzheimers disease (AD), high-fat diet-induced obesity accelerated cognitive decline, which was associated with immune deviations comprising increased splenic frequencies of exhausted CD4+ T effector memory cells and CD4+FOXP3+ regulatory T cells (Tregs). Non-targeted plasma metabolomics identified N-acetylneuraminic acid (NANA), the predominant sialic acid, as the major obesity-induced metabolite in 5xFAD mice, the levels of which directly correlated with Tregs abundance and inversely correlated with cognitive performance. Visceral adipose tissue macrophages were identified by sNuc-Seq as one potential source of NANA. Exposure to NANA led to immune deregulation in middle-aged wild-type mice, and ex vivo in human T cells. Our study identified diet-induced immune deregulation, potentially via sialic acid, as a previously unrecognized link between obesity and AD.

neuroscience↗