Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.10.26.762038

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

Mohanty, S.·Bosworth, S.·Ramaswamy, K.·Natarajan, C.·Krishnan, B.
View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Mohanty, S., Bosworth, S., Ramaswamy, K., Natarajan, C., Krishnan, B.. 2026-10-27. Repeated VU0155069 Treatment Is Associated with Region- and Pathological Stage-Specific Dendritic Spine Remodeling in Female 3xTg-AD Mice. https://doi.org/10.64898/2026.10.26.762038

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Brain representations of visual short-term memories during healthy human aging: occipital decline and frontoparietal compensation

Visual short-term memory declines steeply with age, but the link to neural representations of memory content remains unknown. We used fMRI decoding to relate remembered motion-direction representations in visual and frontoparietal cortex to age and performance, in 115 adults, aged 25-87, from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort. Decoding was strongest in visual cortex, but also significant in frontoparietal regions, with different profiles. Visual representations weakened with memory load and age, and statistically mediated age-related performance decline, especially during recall. This coupling, however, weakened with age: some older adults retained stronger visual representations than performance implied, suggesting impaired access to a partially preserved memory trace. Frontoparietal representations, instead, were largely insensitive to load and strengthened with age during maintenance, partially offsetting performance decline. Therefore, interventions to boost VSTM in older adults might target compensatory frontoparietal representations during memory maintenance, and readout of untapped visual representations at recall.

neuroscience↗
bioRxiv2026

Lexical surprisal drives pupil dilation during continuous story listening

The pupil famously adjusts its dilation in response to light, but its role extends far beyond this basic sensory function. Its fluctuations index arousal and mental effort, beyond luminance-related dynamics, making it a sensitive marker of internal cognitive states. A growing body of work shows that these pupil-linked signals extend beyond the visual domain. However, which processes drive pupil responses in more naturalistic settings remains unclear as most evidence comes from tightly controlled paradigms that strip away the richness of real-world experience. Language offers a uniquely powerful window into this question, as it can allow us to create rich paradigms without having any visual, i.e. luminance, confounds. Moreover, language comprehension hinges on continuous prediction: listeners constantly generate expectations about upcoming input, and the discrepancy between expectation and actual input - contextual prediction error, or surprisal - carries measurable cognitive costs. Here, we tested the hypothesis that pupil-linked arousal indexes these linguistic surprisal signals during naturalistic listening. We recorded pupil responses while volunteers listened to naturalistic spoken stories in darkness, which were either intact or reversed. Reversed speech preserves the acoustics of the signal while destroying its intelligibility. Pupil dilation selectively tracked lexical surprisal within a late window of 1,700 to 2,350 milliseconds following word onset, in forward, but not control, backward speech. These findings indicate that pupil-linked arousal is tuned to global, context-dependent processing, tracking the cognitive cost of updating a predictive model during naturalistic listening.

neuroscience↗
bioRxiv2026

Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease

MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. We test the hypothesis that an endosomal recycling pathway regulated by the interaction of SORL1 with retromer, which is pathogenically disrupted in AD, might drive the neurodegenerative process via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling AD's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, taken together with other findings, the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.

neuroscience↗