New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

An emerging framework for digital mental health design with Indigenous young people: a scoping review of the involvement of Indigenous young people in the design and evaluation of digital mental health interventions.

BACKGROUND: Indigenous young people worldwide possess unique protective factors that support wellbeing. However, they experience mental illness at higher rates than their non-indigenous counterparts. Digital mental health (dMH) resources can increase access to structured, timely, and culturally tailored mental health interventions by reducing structural and attitudinal barriers to accessing treatment. The involvement of Indigenous young people in dMH resource development is recommended, however, no guidelines exist on how this can best be facilitated. METHODS: A scoping review examining processes to involve Indigenous young people in developing or evaluating dMH interventions was conducted. Studies reported between 1990 and 2023 involving Indigenous young people aged 12-24 years, originating from Canada, the USA, New Zealand, and Australia, in the development or evaluation of dMH interventions were eligible for inclusion. Following a three-step search process, four electronic databases were searched. Data were extracted, synthesized, and described under three categories: dMH intervention attributes, study design, and alignment with research best practice. Best practice recommendations for Indigenous research and participatory design principles derived from the literature were identified and synthesised. Included studies were assessed against these recommendations. Consultation with two Senior Indigenous Research Officers ensured Indigenous worldviews informed analysis. RESULTS: Twenty-four studies describing eleven dMH interventions met inclusion criteria. Studies included formative, design, pilot, and efficacy studies. Overall, most included studies demonstrated a high degree of Indigenous governance, capacity building, and community benefit. All studies adapted their research processes to ensure that local community protocols were followed and most aligned these within an Indigenous research paradigm. Formal agreements regarding existing and created intellectual property and implementation evaluations were rare. Outcomes were the primary focus of reporting, with limited detailed descriptions of governance and decision-making processes or strategies for managing predictable tensions between co-design stakeholders. CONCLUSIONS: This study identified recommendations for undertaking participatory design with Indigenous young people and evaluated the current literature against these criteria. Common gaps were evident in the reporting of study processes. Consistent, in-depth reporting is needed to allow assessment of approaches for this hard-to-reach population. An emergent framework, informed by our findings, for guiding the involvement of Indigenous young people in the design and evaluation of dMH tools is presented. TRIAL REGISTRATION: Available via osf.io/2nkc6.

Decision-making about dialysis: Beyond just dialysis or death.

Nearly half of the persons receiving dialysis in the United States are aged 65 years or older. Kidney failure occurs most frequently in older adults, and typically triggers a discussion regarding dialysis treatment. In this Special Article, we describe the journey of Mr. Howard Russell, an older adult who experienced kidney failure and underwent dialysis. Using the experience of Mr. Russell, we illustrate the complexity of dialysis decision-making, including how disease trajectory and health policy can potentially impede older adults from achieving "what matters." Our intent is to provide guidance regarding these barriers and support to clinicians who are sharing similar journeys with older adults making decisions about dialysis. Based on Mr. Russell's journey, we suggest that when discussing dialysis with an older adult, four points be considered: (1) recognize if dialysis is needed long-term; (2) understand what matters for the older adult; (3) sync the treatment plan when what matters changes; and (4) set up with resources for kidney failure, which is limited but evolving.

Antioxidants Rescue Mitochondrial Transport in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells.

Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer's disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD.

Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell.

Mitochondrial dysfunction is an early pathological feature of Alzheimer's disease (AD). The underlying mechanisms and strategies to repair it remain unclear. Here, we demonstrate for the first time the direct consequences and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in AD. Using cytoplasmic hybrid (cybrid) neurons with incorporated platelet mitochondria from AD and age-matched non-AD human subjects into mitochondrial DNA (mtDNA)-depleted neuronal cells, we observed that AD cybrid cells had significant changes in morphology and function; such changes associate with altered expression and distribution of dynamin-like protein (DLP1) and mitofusin 2 (Mfn2). Treatment with antioxidant protects against AD mitochondria-induced extracellular signal-regulated kinase (ERK) activation and mitochondrial fission-fusion imbalances. Notably, inhibition of ERK activation not only attenuates aberrant mitochondrial morphology and function but also restores the mitochondrial fission and fusion balance. These effects suggest a role of oxidative stress-mediated ERK signal transduction in modulation of mitochondrial fission and fusion events. Further, blockade of the mitochondrial fission protein DLP1 by a genetic manipulation with a dominant negative DLP1 (DLP1(K38A)), its expression with siRNA-DLP1, or inhibition of mitochondrial division with mdivi-1 attenuates mitochondrial functional defects observed in AD cybrid cells. Our results provide new insights into mitochondrial dysfunction resulting from changes in the ERK-fission/fusion (DLP1) machinery and signaling pathway. The protective effect of mdivi-1 and inhibition of ERK signaling on maintenance of normal mitochondrial structure and function holds promise as a potential novel therapeutic strategy for AD.

Credentialing of practitioners of botanical medicine.

This article discusses how practitioners, regardless of other professional licenses they may hold, could be credentialed in botanical medicine. The article reviews the field of clinical botanical medicine and the history and modern status of botanical medicine, as well as organizations currently involved in botanical medicine credentialing. Many different types of professionals prescribe botanical medicines, and the potential for collaboration among them is great. The current trend treats botanical medicine as a narrow subdivision of allopathic medicine and does not acknowledge the breadth, depth, and diversity of botanical medicine and ultimately will not provide maximum benefits for patients. An alternative approach that instead credentials practitioners skilled in the use of a wide variety of botanical medicines in a responsible, scientific fashion is presented.