Abstract Background Age is the principal risk factor for neurodegeneration in both retina and brain. The brain share many biological properties; thus, insights into retinal aging degeneration may shed light onto similar processes Genetic makeup strongly influences susceptibility to age-related disease. However, studies investigating have not sufficiently accounted genetic diversity. Therefore, examining molecular across different backgrounds will enhance our understanding of human-relevant...

Abstract Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, important risk factor for glaucoma, leads to RGC axonal injury at optic nerve head. This insult triggers molecularly distinct cascades governing somal apoptosis and degeneration. The molecular mechanisms activated hypertensive that drive both degeneration are incompletely understood. cellular response endoplasmic reticulum stress...

Endothelin (EDN, also known as ET) signaling has been suggested to be an important mediator of retinal ganglion cell (RGC) death in glaucoma. Antagonism EDN receptors (EDNRA and EDNRB, ET-A ET-B) prevented RGC mouse models chronic ocular hypertension, intravitreal injection ligand was sufficient drive death. However, it remains unclear which types ligands directly affect elicit Multiple the retina optic nerve express EDNRA EDNRB thus could respond context Here, we systematically deleted Edn...

Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. activation occurs in two stages including translocation latent to the mitochondrial outer membrane (MOM) and then permeabilization MOM facilitate release apoptotic signaling molecules. As critical component RGC death, an attractive target for neuroprotective therapies understanding kinetics mechanisms controlling this process RGCs potentially valuable informing development strategy.

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons retina. Multiple lines evidence show endothelin (EDN, also known as ET) system important in glaucomatous neurodegeneration. To date, molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target JNK signaling) and endoplasmic reticulum stress effector DNA damage inducible...

Abstract Injury to the axons of retinal ganglion cells (RGCs) is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target c-Jun N-terminal kinases, JNKs) and DDIT3/CHOP (a mediator endoplasmic reticulum stress response) have been shown control majority proapoptotic signaling after mechanical axonal injury RGCs other models downstream transcriptional networks controlled by DDIT3, which are critical for RGC death, however, not well defined. To...

Abstract In recent years, microglia have been highlighted for playing integral roles in neurodegenerative diseases, like glaucoma. To better understand the role of during chronic ocular hypertension, we depleted from aged (9-12 months old) DBA/2J (D2) mice, which exhibit age-related increases intraocular pressure, using a dietary CSF1R antagonist, PLX5622. Retinal ganglion cell (RGC) somas were counted, and optic nerve cross-sections stained assessed glaucomatous damage. Sustained...

Abstract Background Age is the principal risk factor for neurodegeneration in both retina and brain. The brain share many biological properties; thus, insights into retinal aging degeneration may shed light onto similar processes Genetic makeup strongly influences susceptibility to age-related disease. However, studies investigating have not sufficiently accounted genetic diversity. Therefore, examining molecular across different backgrounds will enhance our understanding of human-relevant...

We report on the development of fluorescence Gabor domain optical coherence microscopy (Fluo GD-OCM), a combination GD-OCM with laser scanning confocal (LSCFM) for synchronous micro-structural and imaging. The dynamic focusing capability provided adaptive illumination environment both modalities without any mechanical movement. Using Fluo GD-OCM, we imaged ex vivo DsRed-expressing cells in brain transgenic mouse, as well Cy3-labeled ganglion astrocytes from mouse retina. self-registration...

Summary Metabolic syndrome (MetS) puts patients more at risk for neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia are implicated causal factors in AD, however, the effect of MetS on microglia has not been characterized. To address this, we contrasted New Zealand Obese (NZO) with C57BL/6J (B6J) mice combination a high fat/high sugar diet (HFD). Irrespective diet, NZO displayed broader array MetS-relevant phenotypes compared to B6J fed HFD. Single cell RNA-sequencing...

Precise regulation of protein phosphorylation is critical for many cellular processes, and dysfunction in this process has been linked to various neurological disorders diseases. Protein phosphatase 1 (PP1) a ubiquitously expressed serine/threonine with three major isoforms, (α, β, γ) hundreds known substrates. Previously, we reported that PP1α PP1γ are essential the role PP1 synaptic physiology learning/memory, while PP1β displayed surprising opposing function.

Abstract Glaucoma is characterized by programmed cell death of retinal ganglion cells (RGCs) after axonal injury. Several studies have shown the cell-intrinsic drivers RGC degeneration act in a compartment-specific manor. Recently, transcription factors JUN and DDIT3 were identified as critical hubs regulating somal loss mechanical It possible DDIT3/JUN activity initiates mechanisms glaucoma. Alternatively, may downstream inciting degenerative only drive loss. The MAP2Ks MKK4 MKK7 control...

Abstract Background Cerebral amyloid angiopathy (CAA) co‐occurs with neurodegeneration in Alzheimer’s disease (AD). CAA is absent many AD mouse models, rendering difficult to study. Previous work has shown wild‐derived WSB/EiJ (WSB) mice over‐expressing APP/PS1 had increased CAA, and thus may be useful investigating CAA‐causing mechanisms. Here, genetic backgrounds susceptibility (WSB. ) resilience (B6. are leveraged map CAA‐susceptibility loci. Furthermore, blood brain barrier (BBB)...

Background Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. activation occurs in two stages including translocation latent to the mitochondrial outer membrane (MOM) and then permeabilization MOM facilitate release apoptotic signaling molecules. As critical component RGC death, an attractive target for neuroprotective therapies understanding kinetics mechanisms controlling this process RGCs potentially valuable informing development...

Abstract Background APOE e4 is the greatest risk factor for late‐onset Alzheimer’s disease (AD), accounting ∼30% of genetic and significantly decreasing age onset. implicated to play central roles across multiple pathways such as neuroinflammation, lipid metabolism vascular health. Current mechanistic work has introduced humanized alleles in mouse models AD on a single laboratory strain, C57BL/6J (B6). Recent from our lab taken advantage genetically diverse wild‐derived strains which were...

Abstract Background Disease‐modifying treatments for Alzheimer’s disease and related dementias (ADRD) will be most effective early in the process. Clinical use of these therapies require practical, widely accessible biomarkers. Plasma‐based protein biomarkers hold promise identifying core AD pathology, but this complex likely requires other markers to identify people at highest risk progression dementia. Studies support eye exams as a synergistic strategy since retinal imaging would cost...

Abstract Background Cerebral amyloid angiopathy (CAA) co‐occurs with cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). We have shown wild‐derived WSB/EiJ (WSB) mice transgenic for APP/PS1 robustly developed CAA are thus a useful tool to investigate the mechanisms driving CAA. It has been hypothesized that loss of blood brain barrier (BBB) integrity causes improper clearance vascular deposition. One mechanism by which this is possible deactivation (loss phosphorylation)...

Abstract Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, important risk factor for glaucoma, leads to RGC axonal injury at optic nerve head. This insult triggers molecularly distinct cascades governing somal apoptosis and degeneration. The molecular mechanisms activated hypertensive that drive both degeneration are incompletely understood. cellular response endoplasmic reticulum stress...