Biology subjects

Jury-Garfe, N.

Publications and source records attributed to Jury-Garfe, N..

5 recordsLinked to original sources

bioRxiv2026

Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease

Tau is a microtubule-associated protein with diverse roles in the healthy brain but contributes to neurodegenerative disorders when dysregulated. Although tau ablation has shown protective effects in several disease models, how its absence confers this protection remain unclear. Here, we performed and analyzed single-nucleus RNA sequencing on cortices of aged tau knockout (Mapt-/-) mice in a wild type background as well as in a vascular amyloid model to evaluate the effect on disease context. Comparisons in a wild type setting revealed that tau ablation induced compensatory remodeling across multiple cell types. Excitatory neurons expanded into a distinct subtype with unique glutamatergic signaling, astrocytes adopted synaptoprotective states, oligodendrocytes upregulated genes supporting connectivity and plasticity, and microglia engaged structural remodeling programs. In contrast, in disease, tau removal not only restored functions disrupted by vascular amyloid pathology, but also generated new phenotypes. Excitatory neurons rewired receptor and postsynaptic signaling, astrocytes and oligodendrocytes recovered wild-type-like gene programs related to neurotransmitter cycling, synaptic support, and myelin integrity, and microglia reprogrammed toward sensing and mounting responses. Together, these findings demonstrate that tau ablation reshapes brain cellular programs in a context-dependent manner, exerting adaptive responses in the otherwise healthy brain while restoring homeostatic functions under vascular amyloid pathology. These results position tau as a key regulator of neuronal-glial network balance and highlight the importance of understanding how tau influences distinct cellular programs within specific disease environments.

neuroscience↗

bioRxiv2026

TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, is present in 85-95% of Alzheimers disease (AD) patients. Despite its high prevalence, the mechanisms by which CAA contributes to neurodegeneration remain poorly understood. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed exclusively by microglia, regulates activation, phagocytosis, and amyloid clearance, thereby shaping neuroinflammation. Loss-of-function mutations in TREM2 markedly increase AD risk, but its role in CAA pathology remains unknown. To investigate this, we crossed the Familial Danish Dementia (Tg-FDD) mouse model, which accumulates robust vascular amyloid, with TREM2 knockout (TREM2KO) mice to generate Tg-FDD/TREM2KO animals. Histological and transcriptomic analyses revealed region-specific effects of TREM2 deficiency. In the cortex, TREM2 loss markedly reduced vascular amyloid deposition, accompanied by decreased tau pathology. In contrast, in the cerebellum, TREM2 deletion exacerbated vascular amyloid accumulation, promoted astrogliosis, and enhanced tau pathology. Transcriptomic profiling further identified distinct neuroinflammatory signatures between cortex and cerebellum, particularly in cytokine signaling, matrix remodeling, and lipid metabolism. Together, these findings demonstrate that TREM2 deficiency leads to region-specific effects on CAA, revealing extensive regional variability in vascular amyloid pathology and underscoring the importance of considering these differences when developing TREM2-based therapies.

neuroscience↗

bioRxiv2025

Tau-seed interactome analysis reveals distinct functional signatures in Alzheimer's disease across model systems.

Tau aggregates propagate through the brain in a prion-like manner in Alzheimers disease (AD) and other tauopathies, but the molecular identity and functional partners of the seeding-competent Tau species remain poorly defined. Here, we present an unbiased proteomic profiling of a high-molecular-weight (HMW) Tau-seed isolated from AD patient brains. We contrast this interactome with that of a biochemically similar, seeding-incompetent HMW-Tau species from age-matched healthy controls. Despite comprising less than 5% of total Tau in the brain, Tau-seed associates with a distinct set of proteins enriched in synaptic, mitochondrial, and vesicle-trafficking functions. Cross-species functional screening in Drosophila and mouse models identifies interactors that modulate Tau toxicity and seeding. Spatially resolved analysis of postmortem AD brains reveals heterogenous co-deposition of these proteins with Tau aggregates, suggesting functionally distinct Tau-seed complexes. Together, this dataset provides a framework for understanding selective Tau-seed toxicity and identifies candidate regulators of Tau propagation with therapeutic potential.

neuroscience↗

bioRxiv2024

Phosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation.

Pathological aggregation and propagation of hyperphosphorylated and aberrant forms of tau are critical features of the clinical progression of Alzheimers disease and other tauopathies. To better understand the correlation between these pathological tau species and disease progression, we profiled the temporal progression of tau seeding activity and the levels of various phospho- and conformational tau species in the brains of two mouse models of human tauopathies. Our findings indicate that tau seeding is an early event that occurs well before the appearance of AT8-positive NFT. Specifically, we observed that tau phosphorylation in serine 214 (pTau-Ser214) positively correlates to tau seeding activity during disease progression in both mouse models. Furthermore, we found that the histopathology of pTau-Ser214 appears much earlier and has a distinct pattern and compartmentalization compared to the pathology of AT8, demonstrating the diversity of tau species within the same region of the brain. Importantly, we also observed that preventing the phosphorylation of tau at Ser214 significantly decreases tau propagation in mouse primary neurons, and seeding activity in a Drosophila model of tauopathy, suggesting a role for this tau phosphorylation in spreading pathological forms of tau. Together, these results suggest that the diverse spectrum of soluble pathological tau species could be responsible for the distinct pathological properties of tau and that it is critical to dissect the nature of the tau seed in the context of disease progression.

neuroscience↗

bioRxiv2023

Enhanced microglial dynamics and paucity of tau seeding in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer 's disease

Asymptomatic Alzheimers disease (AsymAD) describes the status of subjects with preserved cognition but with identifiable Alzheimers disease (AD) brain pathology (i.e. A{beta}-amyloid deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the underlying mechanisms of resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation, as well as an increase in microglia surrounding this last type. In AsymAD cases we found less pathological tau aggregation in dystrophic neurites compared to AD and tau seeding activity comparable to healthy control subjects. We used spatial transcriptomics to further characterize the plaque niche and found autophagy, endocytosis, and phagocytosis within the top upregulated pathways in the AsymAD plaque niche, but not in AD. Furthermore, we found ARP2, an actin-based motility protein crucial to initiate the formation of new actin filaments, increased within microglia in the proximity of amyloid plaques in AsymAD. Our findings support that the amyloid-plaque microenvironment in AsymAD cases is characterized by microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared to AD. These two mechanisms can potentially provide protection against the toxic cascade initiated by A{beta} that preserves brain health and slows down the progression of AD pathology.

neuroscience↗