👤 James T Handa

Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are neurodegenerative conditions that afflict millions of elderly people around the world. AMD is a progressive retinal disorder that leads to central vision loss whereas AD primarily causes cognitive decline and behavioral changes. While each disease has distinct clinical manifestations, the accumulation of extracellular amyloid-β is a common histopathologic finding. Similarly, cerebral amyloid angiopathy (CAA), a vascular condition that can exist independent or with AD, is characterized by the accumulation of amyloid-β in cerebral blood vessels. While significant investigation of the pathophysiologic links between AMD and AD has been conducted, the underlying similarities and differences in the pathobiology of AMD and CAA has not been considered. In this review, we discuss the common pathological features of these two conditions. We then discuss the similar pathobiology that involves cholesterol metabolism, apolipoprotein E, amyloid-β, and complement mediated inflammation. At the same time, we discuss key differences in their pathobiology. This discussion sheds new perspective and insights of their pathobiology. Show less

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, is used to treat lymphoplasmacytic lymphoma (LPL). A hallmark complication of LPL is hyperviscosity syndrome (HVS), caused by markedly elevated serum IgM levels. Plasma exchange (PE) is a standard treatment for HVS but may also remove circulating drugs, particularly those with high protein binding, potentially reducing drug exposure and efficacy. Evaluating the impact of PE on the pharmacokinetics of drugs used to treat LPL is important for optimal treatment. We report the case of a 63-year-old man with LPL who presented with acute headache and was diagnosed with HVS. Tirabrutinib (480 mg, once daily) was initiated, and PE was performed the next day because of persistent IgM elevation. To assess the impact of PE on tirabrutinib plasma concentrations, blood samples were collected approximately 3 h prior to PE (C15), immediately before PE (C18), and immediately after PE (C20). The concentrations at C15, C18 and C20 were 33.3, 16.9, and 11.4 ng/mL, respectively. The elimination rate constant (ke) was calculated as 0.226 h⁻¹ before PE and 0.197 h⁻¹ during PE. Based on the pre-PE ke, the predicted post-PE concentration (C20) assuming no PE was approximately 10.6 ng/mL, slightly lower than the observed value. PE appeared to have minimal impact on the tirabrutinib plasma concentration, likely due to its large volume of distribution. Although further cases are needed, this case supports the feasibility of concomitant PE during tirabrutinib therapy without significant compromise of drug efficacy. Show less

Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment. Show less

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD. Show less

17beta-Hydroxysteroid dehydrogenase type 12 (17beta-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17beta-HSD12 expression was also reported in breast carcinomas but its functions have remained unknown. In this study, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases. No significant correlations were detected between 17beta-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17beta-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17beta-HSD12 using cell-based studies. Small interfering RNA-mediated knockdown of 17beta-HSD12 in SK-BR-3 (estrogen receptor-negative breast carcinoma cell line) resulted in significant growth inhibition, which was recovered by the addition of VLCFAs such as arachidonic acid. The status of 17beta-HSD12 immunoreactivity was also correlated with adverse clinical outcome in cyclooxygenase 2 (COX2)-positive breast cancer patients but not in COX2-negative patients. Therefore, these findings indicated that 17beta-HSD12 was not necessarily related to intratumoral E2 biosynthesis, at least in human breast carcinoma, but was rather correlated with production of VLCFAs such as arachidonic acid, which may subsequently be metabolized to prostaglandins by COX2 and result in tumor progression of the patients. Show less

The 17beta-hydroxysteroid dehydrogenases (HSDs) are enzymes that catalyze the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids. 17beta-HSD type 12, the most recently cloned member of this gene family, was classified into the 17beta-HSD family based on sequence homology, rather than steroid catalyzing activity. Meanwhile, it has been reported that 17beta-HSD type 12 may be involved in fatty acid synthesis. To better understand the role of 17beta-HSD type 12 in lipid metabolism, we determined the detailed systemic distribution and tissue localizations of 17beta-HSD type 12, which, due partly to the lack of antibodies, had not yet been studied. We carried out these investigations by quantitative reverse transcription (RT)-PCR, Northern blot analysis, and immunohistochemistry, using an antibody against 17beta-HSD type 12 that we have generated. 17beta-HSD type 12 is highly expressed in organs related to lipid metabolism such as liver, kidney, heart and skeletal muscle. 17beta-HSD type 12 is also detected in endocrine-related organs such as pancreas, pituitary gland, adrenal gland, testis and placenta, and in the gastrointestinal tract, which point to the possible involvement of 17beta-HSD type 12 in the regulation of lipid biosynthesis and steroid metabolism. These results support previous reports and solidify the possibility that 17beta-HSD type 12 may play critical roles in the physiological processes, such as fatty acid synthesis, in addition to the steroid metabolism. Show less