Biology subjects

Ramaswamy, K.

Publications and source records attributed to Ramaswamy, K..

3 recordsLinked to original sources

bioRxiv2026

Repeated VU0155069 Treatment Is Associated with Region- and Pathological Stage-Specific Dendritic Spine Remodeling in Female 3xTg-AD Mice

Background: Alzheimers disease (AD) is increasingly recognized as a disorder of synaptic integrity in which changes in dendritic spine abundance and morphology accompany progressive cognitive dysfunction. Phospholipase D1 (PLD1), a regulator of membrane trafficking and cytoskeletal signaling, is aberrantly elevated in AD-related pathological states (ADRD). Previous studies from our lab demonstrated that repeated VU0155069 treatment promotes functional resilience in female 3xTg-AD mice, including improvements in novel-object recognition, fear-conditioning performance, hippocampal LTP, later-stage LTP and LTD, selected neuropathological outcomes, and most importantly, CA1 spine integrity. Objective: To determine how this previously demonstrated functional resilience is represented structurally across cortical, hippocampal, and amygdalar circuits at earlier and later stages of AD-like pathology. Methods: Female 3xTg-AD mice received vehicle or VU0155069 at 1 mg/kg intraperitoneally every other day for one month beginning at 5 or 11 months of age, with Golgi-Cox analysis at 6 or 12 months, respectively. Age-matched vehicle-treated 3xTg-AD littermates served as the primary comparator for evaluating the structural response to pharmacological attenuation of disease-associated PLD1 signaling. Results: Auditory and visual cortical fields showed selective changes in spine-subtype distribution and morphometry. Hippocampal cornu ammonis (CA)2, CA3, and dentate gyrus (DG) exhibited distinct patterns involving spine abundance, density, and geometry, whereas the central, lateral, and basolateral amygdalar nuclei showed nucleus- and stage-dependent remodeling. Across the multiregional dataset, recurring responses comprised spine-subtype redistribution, changes in spine abundance, and morphometric remodeling rather than uniform structural rescue. Conclusions: VU0155069 engages circuit- and pathological stage-specific forms of dendritic spine remodeling across distributed recognition- and associative-memory networks.

neuroscience↗

bioRxiv2025

PLD1-Dependent Regulation of Synaptic Integrity: Implications for Cognitive Resilience and Alzheimer's Disease Pathogenesis

Dysregulation of Phospholipase D1 (PLD1) has been implicated in the progression of neurodegenerative diseases, including Alzheimers Disease (AD). This study investigated PLD1 signaling in synaptic integrity and cognition during aging and in a late-onset AD mouse model, hypothesizing differential effects of PLD1 modulation on synaptic vulnerability. AAV2-mediated gene transfer was employed to overexpress (PLD1 OXP) or attenuate (PLD1 ATT) PLD1 in aged wild-type (WT) and 3xTg-AD mice. To validate these constructs, differentiated PC12 cells were utilized. Within these cells, a model of post-mitotic neurons, PLD1 OXP exhibited a notable reduction in both the average neurite length and the percentage of neurite-bearing cells. This suggests that elevated PLD1 activity exerts a significant influence on neurite outgrowth. Conversely, PLD1 ATT did not inhibit neurite formation, indicating it is not detrimental at the cellular level. These cellular findings paralleled in vivo observations - electrophysiological studies revealed PLD1 OXP impaired long-term potentiation (LTP) and synaptic transmission, particularly in aged WT mice, whereas PLD1 ATT improved synaptic function in 3xTg-AD mice. Behaviorally, PLD1 ATT enhanced spatial working memory and reduced anxiety-like behavior, notably in 3xTg-AD mice. These results highlight that tight PLD1 regulation is vital for maintaining synaptic integrity and cognitive resilience. Thus, PLD1 attenuation may serve as an important complement to immunotherapeutic approaches by strengthening synaptic resilience in neurodysfunctional states, including AD and related dementia (ADRD).

neuroscience↗

bioRxiv2017

Peptidomimetic blockade of MYB in acute myeloid leukemia

Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, largely due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP)/P300 is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex at micromolar concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, led to the displacement of the MYB:CBP/P300 complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, underwent mitochondrial apoptosis in response to MYBMIM treatment, which could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP/P300 transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.

cancer biology↗