Biology subjects

Ahn, H. J.

Publications and source records attributed to Ahn, H. J..

4 recordsLinked to original sources

bioRxiv2025

Pathological Mechanisms of Motor Dysfunction in Familial Danish Dementia: Insights from a Knock-In Rat Model

Familial Danish Dementia (FDD) is a rare autosomal dominant neurodegenerative disorder caused by a mutation in the integral membrane protein 2B (ITM2b) gene. Clinically, FDD is characterized by cerebral amyloid angiopathy (CAA), cerebellar ataxia, and dementia. Notably, FDD shares several neuropathological features with Alzheimers disease (AD), including CAA, neuroinflammation, and neurofibrillary tangles. In this study, we investigate the pathological mechanisms linking CAA, white matter damage, and motor dysfunction using a recently developed FDD knock-in (FDD-KI) rat model. This model harbors the Danish mutation in the endogenous rat Itm2b gene, along with an App gene encoding humanized amyloid-{beta} (A{beta}). Our analysis revealed substantial vascular Danish amyloid (ADan) deposition in the cerebellar subpial and leptomeningeal vessels of FDD-KI rats, showing an age-related increase comparable to that observed in human FDD patients. Additionally, vascular A{beta} deposits (A{beta}-CAA) were present in FDD-KI rats, but A{beta}-CAA patterns showed some differences between species. Motor function assessments in FDD-KI rats demonstrated age-accelerated motor deficits and gait abnormalities, mirroring the clinical characteristics of FDD patients. To further explore the mechanisms underlying these deficits, we examined cerebellar pathology and found age-related myelin disruption and axonal fiber loss, consistent with postmortem human FDD pathology. Cerebellar demyelination appeared to be driven by neuroinflammation, marked by increased microglial/macrophage activation in response to vascular amyloid deposition. Additionally, we observed extravascular fibrinogen leakage, indicating widespread vascular permeability in both white and gray matter, with fibrinogen deposits surrounding amyloid-positive vessels in aged FDD-KI rats and postmortem FDD cerebellum. These findings suggest that this FDD-KI rat model is the first animal model to recapitulate key neuropathological features of human FDD patients, including both ADan- and A{beta}-type CAA, neuroinflammation, and white matter lesions--pathologies that may underlie the motor and gait impairments seen in the disease.

neuroscience↗

bioRxiv2024

Caveolin-1 and Aquaporin-4 as Mediators of Fibrinogen-Driven Cerebrovascular Pathology in Hereditary Cerebral Amyloid Angiopathy

Cerebral Amyloid Angiopathy (CAA), characterized by amyloid-{beta} (A{beta}) accumulation within perivascular spaces (PVS), contributes to vascular damage and inflammation in Alzheimers disease (AD). Despite its significance, the mechanisms driving A{beta} deposition in PVS and the resulting vascular pathology remain poorly understood. Growing evidence suggests that fibrinogen, the main component in blood clots, interacts with A{beta} and exacerbates inflammation in AD. Fibrinogen also co-deposits with A{beta} in the PVS of CAA-positive vessels in the brains of hereditary CAA patients. However, the mechanisms by which fibrinogen contributes to cerebrovascular impairment remain poorly understood. To investigate this, we used TgSwDI transgenic mice, which develop robust CAA pathology, and observed a significant increase in fibrin(ogen) extravasation and colocalization with A{beta} in the PVS. Moreover, we observed a significant aquaporin-4 (AQP4) depolarization in CAA-laden blood vessels of TgSwDI mice, which correlated with fibrin(ogen)-A{beta} colocalization. Given AQP4 crucial role in A{beta} clearance through glymphatic pathway, its depolarization may disrupt critical A{beta} clearance, thereby exacerbating CAA pathology. Additionally, Caveolin-1, a protein involved in non-specific transcytosis across the endothelium, significantly increased with age in TgSwDI mice and correlated with fibrin(ogen) extravasation. To further explore the relationship between fibrin(ogen) and these cerebrovascular alterations, we depleted fibrinogen in TgSwDI mice using siRNA approach. This intervention resulted in decreased CAA, restored polarized expression of AQP4, reduced caveolin-1 levels, attenuated microglial activation, and improved spatial memory in fibrinogen-depleted TgSwDI mice. These findings suggest that targeting fibrinogen could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology. Significance StatementOur study uncovers the mechanism by which fibrin(ogen)-A{beta} colocalization exacerbates CAA pathology. Our findings highlight the potential link between fibrinogen/ fibrin(ogen)-A{beta} colocalization and AQP4 depolarization thereby exacerbating CAA pathology. The age-dependent increase of endothelial caveolin-1 could facilitate fibrin(ogen) extravasation, assisting the later to binds to A{beta} in the perivascular space which ultimately induce microglial neuroinflammation and AQP4 depolarization, thus exacerbating CAA pathology. Furthermore, fibrinogen depletion could mitigate CAA severity, reduce microglial activation, restore AQP4 polarization and memory impairment. These results suggest that targeting fibrinogen and caveolin-1-mediated transcytosis may offer new strategies to address CAA-associated cerebrovascular pathology.

neuroscience↗

bioRxiv2021

Fiberoptic Probe For Hemodynamic Spectroscopy in Freely Moving Mice Shows Cerebrovascular Dysregulation In Alzheimers and Glioma Models

SignificanceCerebral vascular reactivity is critical parameters of brain homeostasis in health and disease, but the investigational value of brain oxymetry is diminished by anesthesia and mechanical fixation of the mouse scull. AimWe needed to reduce the physical restrictivity of hemodynamic spectroscopy to enable Alzheimers disease (AD) studies in freely-moving mice. ApproachWe combined spectroscopy, spectral analysis software and a magnetic, implantable device to measure vascular reactivity in unanesthetized, freely-moving mice. We measured cerebral blood volume fraction (CBVF) and oxygen saturation (SO2). ResultsWe validated that our system could detect delayed cerebrovascular recovery from hypoxia in an orthotopic xenograft glioma model under anesthetized condition and we also found increased CBVF and impaired vascular reactivity during hypercapnia in a freely-moving mouse model of AD compared to wild-type littermates. ConclusionsOur optomechanical approach to reproducibly getting light into and out of the brain enabled us to successfully measure CBVF and SO2 during hypercapnia in unanesthetized freely-moving mice. We present hardware and software enabling oximetric analysis of metabolic activity, which provides a safe and reliable method for rapid assessment of vascular reactivity in murine disease models as well as CBVF and SO2.

neuroscience↗

bioRxiv2018

Clathrin-coated Pits are Shredded Organelles Presorting Receptors in the Plasma Membrane

A myriad of receptor types crowds the plasma membrane of cells. Here, we revealed that clathrin-coated pits (CCPs) presort receptors to modulate receptor activation on the plasma membrane. We visualized individual molecules of receptors, including epidermal growth factor receptor (EGFR), ErbB2, transferrin receptor (TfR), and beta2-adrenergic receptors ({beta}2-AR), inside a single CCP in a living cell using single-molecule diffusivity-based colocalization analysis. The spatially distinct subsets of CCPs selectively allocated for these receptors were observed in a resting state. The EGFR pre-allocated CCP subset was partially shared with that for ErbB2, whereas the EGFR and TfR pre-allocated CCP subsets were mutually exclusive. PICALM was necessary for the pre-allocation of CCPs for EGFR. Furthermore, EGFR dimerization was markedly elevated inside the pre-allocated CCP subset after dynamin recruitment. The pre-sorting function of CCPs provides an efficient mechanism to control competition and cooperation between receptors on the crowded plasma membrane.\n\nOne Sentence SummaryClathrin-coated pits are small-sized organelles pre-sorting receptor kinds to modulate receptor activation on the crowded plasma membrane.

cell biology↗