Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer's Disease Mice.

Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer's disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain.

Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages.

A comparative analysis of cone photoreceptor morphology in bowhead and beluga whales.

The cetacean visual system is a product of selection pressures favoring underwater vision, yet relatively little is known about it across taxa. Previous studies report several mutations in the opsin genetic sequence in cetaceans, suggesting the evolutionary complete or partial loss of retinal cone photoreceptor function in mysticete and odontocete lineages, respectively. Despite this, limited anatomical evidence suggests cone structures are partially maintained but with absent outer and inner segments in the bowhead retina.

Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aβ protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aβ exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection.

Genetically enhancing the expression of chemokine domain of CXCL1 fails to prevent tau pathology in mouse models of tauopathy.

Background: Fractalkine (CXCL1) and its receptor (CXCR1) play an important role in regulating microglial function. We have previously shown that Cxcr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CXCL1 is essential in regulating neuronal tau pathology.

Nodes of Ranvier in Glaucoma.

Retinal ganglion cell axons of the DBA/2J mouse model of glaucoma, a model characterized by extensive neuroinflammation, preserve synaptic contacts with their subcortical targets for a time after onset of anterograde axonal transport deficits, axon terminal hypertrophy, and cytoskeletal alterations. Though retrograde axonal transport is still evident in these axons, it is unknown if they retain their ability to transmit visual information to the brain. Using a combination of in vivo multiunit electrophysiology, neuronal tract tracing, multichannel immunofluorescence, and transmission electron microscopy, we report that eye-brain signaling deficits precede transport loss and axonal degeneration in the DBA/2J retinal projection.

Detection of single mRNAs in individual cells of the auditory system.

Gene expression analysis is essential for understanding the rich repertoire of cellular functions. With the development of sensitive molecular tools such as single-cell RNA sequencing, extensive gene expression data can be obtained and analyzed from various tissues. Single-molecule fluorescence in situ hybridization (smFISH) has emerged as a powerful complementary tool for single-cell genomics studies because of its ability to map and quantify the spatial distributions of single mRNAs at the subcellular level in their native tissue.

Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration.

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-, on a ketogenic diet to encourage mitochondrial function.

Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma.

Whether to stage degeneration or investigate early pathology in glaucoma, examination of axonal structure and function is essential. There are a wide variety of methods available to investigators using animal models of glaucoma, with varying utilities depending on the questions asked. Here, we describe the use of anterograde neuronal tract tracing using cholera toxin B (CTB) for the determination of axon transport integrity of the retinofugal projection.

TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.

Background: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular.

Results: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy.

MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype.

Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP.

Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus.

Neuropathy is a major diabetic complication. While the mechanism of this neuropathy is not well understood, it is believed to result in part from deficient nerve regeneration. Work from our laboratory established that gp130 family of cytokines are induced in animals after axonal injury and are involved in the induction of regeneration-associated genes (RAGs) and in the conditioning lesion response.

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma.

Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins, and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma.

Assessment of alkoxylphenacyl-based polycarbonates as a potential platform for controlled delivery of a model anti-glaucoma drug.

Treatment strategies for glaucoma will benefit from injectable and/or implantable delivery systems that can achieve sustained delivery of neuroprotective agents (to the posterior segment) and/or intraocular pressure lowering drugs (to the anterior segment). In this regard, we have evaluated the suitability of a new polymer (alkoxylphenacyl-based polycarbonates copolymer with polycaprolactone; AP-PCL 20% w/w) as a platform for ocular drug delivery. Brimonidine tartrate (BRT) was applied as a model anti-glaucoma drug.

Persistence of intact retinal ganglion cell terminals after axonal transport loss in the DBA/2J mouse model of glaucoma.

Axonal transport defects are an early pathology occurring within the retinofugal projection of the DBA/2J mouse model of glaucoma. Retinal ganglion cell (RGC) axons and terminals are detectable after transport is affected, yet little is known about the condition of these structures. We examined the ultrastructure of the glaucomatous superior colliculus (SC) with three-dimensional serial block-face scanning electron microscopy to determine the distribution and morphology of retinal terminals in aged mice exhibiting varying levels of axonal transport integrity.

Decreased Energy Capacity and Increased Autophagic Activity in Optic Nerve Axons With Defective Anterograde Transport.

Purpose: Autophagy is a critical process, compromised in neurodegenerative disease, by which terminally differentiated cells like neurons manage cytoskeletal and organelle turnover. How autophagy relates to associated neurodegenerative pathologies remain unclear. We examined autophagy in optic neuropathy by investigating cytoskeletal degradation, mitochondria, and autophagic vesicles in the DBA2/J mouse model of glaucoma exhibiting differing levels of axon transport functionality.

Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.

Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration.

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid.

Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma.

Background: Neuroinflammation-astrogliosis, microglial activation, and changes in cytokine signaling-is a prominent feature of neurodegenerative disorders. Glaucoma is a group of chronic neurodegenerative conditions that make up the leading cause of irreversible blindness worldwide. Neuroinflammation has been postulated to play a significant role in the pathogenesis and progression of glaucomatous neurodegeneration.

Central visual pathways in glaucoma: evidence for distal mechanisms of neuronal self-repair.

As in other age-related neurodegenerative diseases, progression of neurodegeneration in glaucoma involves early axonopathy. In glaucoma, this is marked by degradation of active transport along retinal ganglion cell (RGC) axons projecting from the retina to the brain. In experimental systems, transport degradation occurs first in the most distal site in the RGC projection, the superior colliculus (SC) of the midbrain.

Sensory Hairs in the Bowhead Whale, Balaena mysticetus (Cetacea, Mammalia).

We studied the histology and morphometrics of the hairs of bowhead whales (Balaena mysticetus). These whales are hairless except for two patches of more than 300 hairs on the rostral tip of the lower lip and chin, the rostral tip of the upper lip, and a bilateral row of approximately ten hairs caudal to the blowhole. Histological data indicate that hairs in all three of these areas are vibrissae: they show an outermost connective tissue capsule, a circumferential blood sinus system surrounding the hair shaft, and dense innervation to the follicle.

Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma.

Axonal transport deficits have been reported as an early pathology in several neurodegenerative disorders, including glaucoma. However, the progression and mechanisms of these deficits are poorly understood. Previous work suggests that anterograde transport is affected earlier and to a larger degree than retrograde transport, yet this has never been examined directly in vivo.

Abnormal metal levels in the primary visual pathway of the DBA/2J mouse model of glaucoma.

The purpose of this study was to determine metal ion levels in central visual system structures of the DBA/2J mouse model of glaucoma. We used inductively coupled plasma mass spectrometry (ICP-MS) to measure levels of iron (Fe), copper (Cu), zinc (Zn), magnesium (Mg), manganese (Mn), and calcium (Ca) in the retina and retinal projection of 5-month (pre-glaucomatous) and 10-month (glaucomatous) old DBA/2J mice and age-matched C57BL/6J controls. We used microbeam X-ray fluorescence (μ-XRF) spectrometry to determine the spatial distribution of Fe, Zn, and Cu in the superior colliculus (SC), which is the major retinal target in rodents and one of the earliest sites of pathology in the DBA/2J mouse.

Development and validation of an LC-MS/MS method for determination of the L-type voltage-gated calcium channel/NMDA receptor antagonist NGP1-01 in mouse serum.

NGP1-01 (8-benzylamino-8,11-oxapentacyclo[5.4.0.