The apolipoprotein E (APOE) - ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) accumulation. We recently ...demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aβ accumulation by altering Aβ clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood–brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the brain Aβ efflux index method, we found that blood–brain barrier-mediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances brain-to-blood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain.
The influence of three deposition strategies on the fatigue crack growth behaviour of Wire + Arc Additive Manufactured (WAAM) Ti–6Al–4V has been investigated in the as-built condition. Test samples ...were prepared using single pass, parallel pass, and oscillation deposition strategies and tested with cracks propagating parallel and normal to the plane of deposition. Due to the higher local heat input, the oscillation build exhibited a significantly coarser columnar β grain structure as well as a coarser transformation microstructure, compared to the single pass and parallel pass builds, which were very similar. Among the three build methods, the lowest crack growth rates were found with the oscillation build. The crack growth data was found to broadly fall between that of a recrystallized α (mill-annealed) and β annealed wrought material, with the oscillation strategy build behaving more similarly to a β annealed microstructure. The fatigue crack growth rate was lower when cracks were propagated perpendicular to the build layers. For each build strategy, a greater microstructural influence on crack growth rate was found at lower levels of stress intensity factor range (<25 MPa m1/2). However, the anisotropy and scatter in the data was much more significant in the case of the oscillation build. These differences have been attributed to the stronger α microtexture heterogeneity present in the oscillation build, which led to a greater crack deflection and bifurcation, giving rise to lower crack growth rates and a higher sensitivity to the anisotropy caused by the directional β grain structure.
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE ...affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60-80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for ...tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.
•Complex polygenic information regarding BD is well understood by recipients when provided in the context of a genetic counselling encounter.•People living with BD may benefit from polygenic testing ...to alleviate guilt and blame.•Receiving an unexpected test result may cause transient shock and/or distress.•Individuals may choose not to receive results given their stage of life or recovery.•Future providers of polygenic testing for BD may now better understand its impact.
Polygenic risk scores (PRSs) summarise genetic risk in complex genetic disorders such as bipolar disorder (BD). The aim of this study was to gain in-depth, nuanced information regarding the understanding and experience of receiving a PRS for BD from individuals who already have a BD diagnosis.
Participants from a previous genetics study were invited to receive their PRS in a face-to-face consultation with a genetic counsellor or psychiatrist. Four weeks later, semi-structured interviews were conducted, with 14 ‘acceptors’ (those who chose to receive their PRS) and 4 ‘decliners’ (those who did not wish to receive their PRS).
Four themes were developed: (1) An easy decision, (2) A positive experience, (3) The grey area, and (4) The future is exciting and frightening. Despite some reported initial shock and distress, all acceptors described the experience of receiving their PRS as a positive one. It allowed them to better understand their condition and/or reduced feelings of self-blame. Decliners chose not to receive their results because of a lack of perceived usefulness or concern that PRS may hinder personal recovery.
Given the qualitative design of the study, statistically valid generalisations cannot be undertaken, nor can causal relationships be established.
PRS for BD were generally well accepted and understood. Knowledge regarding the impact of PRS for BD ensures that counselling frameworks are responsive to patient needs as well as informing education for psychiatrists and genetic counsellors, who will play pivotal roles in future polygenic testing provision.
Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the ...consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.
People with a family history of major depressive disorder (MDD) or bipolar disorder (BD) report specific psychoeducational needs that are unmet by existing online interventions. This trial aimed to ...test whether an interactive website for people at familial risk for depression (intervention) would improve intention to adopt, or actual adoption of, depression prevention strategies (primary outcome) and a range of secondary outcome measures.
In this cluster randomised trial, primary care practises were randomised to either provide the link to the intervention or the control website. Primary health care attendees were invited by letter to opt into this study if they had at least one first-degree relative with MDD or BD and were asked to complete online questionnaires at baseline and 2-week follow-up.
Twenty general practices were a randomized, and 202 eligible patients completed both questionnaires. Thirty-nine (19.3%) of participants were male and 163 (80.7%) female. At follow-up, compared to controls, the intervention group: (i) were more likely to intend to undergo, or to have actually undergone, psychological therapies (OR = 5.83, 95% CI: 1.58-21.47, p = .008); (ii) had better knowledge of depression risk factors and prevention strategies (mean difference = 0.47, 95% CI: 0.05-0.88, p = .029); and (iii) were more likely to accurately estimate their lifetime risk of developing BD (mean difference = 11.2, 95% CI: -16.52- -5.73, p < .001). There were no statistically significant between-group differences in change from baseline to follow up for any of the remaining outcome measures (Patient Health Questionnaire, Perceived Devaluation-Discrimination Questionnaire and Perceived Risk of Developing MDD).
The opt-in nature of the study may have led to participation bias, e.g. underrepresentation of males, and hence may limit generalisability to the broader population at familial risk for depression. This is the first website internationally focusing specifically on informational needs of those at familial risk of depression. Our interactive website can play an important role in improving the outcomes of individuals at familial risk for depression. Testing the intervention in other settings (e.g. psychology, psychiatry, genetic counselling) appears warranted.
The study was prospectively registered with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12613000402741 ).
The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model ...of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.
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