Biology subjects

Levendosky, E.

Publications and source records attributed to Levendosky, E..

3 recordsLinked to original sources

bioRxiv2026

PS FAD mutants and γ-secretase inhibition accumulate VEGFR2-derived peptide VCTF1 suppressing brain VEGFR2 dimerization, angiogenesis and neuroprotection.

Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows that most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenesis and neuroprotection. Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces the membrane-bound {gamma}-secretase substrate VEGFR2/CTF1 (called VCTF1), comprising the transmembrane and intracellular domains of VEGFR2. VCTF1 binds full-length VEGFR2 monomers suppressing its dimerization a function that is required for VEGFR2 activation and downstream angiogenesis and neuroprotection. Presenilin1 (PS1) Familial Alzheimers disease (FAD) mutants exert dominant negative effects on the {gamma}-secretase processing of VCTF1 increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation and downstream VEGFR2 signaling, endothelial cell functions and angiogenesis. {gamma}-Secretase inhibitors or PS1 reduction have similar effects on VCTF1 accumulation and VEGFR2 dimerization/activation and downstream signaling and functions as PS1 FAD mutants. Moreover, PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and abolish VEGF-A-induced neuroprotection and cognition. Together, these data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brains VEGF-A-/VEGFR2 angiogenic and neuroprotection systems. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Our data reveal a pathway through which FAD mutants may promote dementia by increasing accumulation of VCTF1 and decreasing angiogenesis, neuroprotection, and cognition, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.

neuroscience↗

bioRxiv2026

Three immunoregulatory signatures define non-productive HIV infection in CD4+ T memory stem cells

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4+ T cells during the first round of infection remains, however, incomplete. In this study, we leveraged the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns that are upregulated in non-productively infected primary CD4+ T memory stem cells (TSCM). We found that CD4+ TSCM harboring non-productive proviruses displayed a distinct transcriptomic signature comprising 118 upregulated genes. This non-productive expression profile was distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4+ T cells harboring non-productive proviruses were CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Intracellular flow cytometry-based analyses confirmed that non-productively infected CD4+ TSCM cells were enriched for CCL22 and IDO1 co-expression compared to the other CD4+ memory subsets, underscoring a clear CD4+ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4+ TSCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.

microbiology↗

bioRxiv2024

Tissue determinants of the human T cell receptor repertoire.

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed from peripheral blood. We single-cell sequenced 5.7 million T cells from ten donors autologous blood and tonsils and sought to answer key questions about T cell receptor biology previously unanswerable by smaller-scale experiments. We identified distinct clonal expansions and distributions in blood compared to tonsils, with surprisingly low (1-7%) clonal sharing. These few shared clones exhibited divergent phenotypes across bodily sites. Analysis of antigen-specific CD8 T cells revealed location as a main determinant of frequency, phenotype, and immunodominance. Finally, diversity estimates from the tissue recalibrates current repertoire diversity estimates, and we provide a refined estimate of whole-body repertoire. Given the tissue-restricted nature of T cell phenotypes, functions, differentiation, and clonality revealed by this dataset, we conclude that tissue analyses are crucial for accurate repertoire analysis and monitoring changes after perturbing therapies.

immunology↗