Background Human genetic association studies point to immune response and lipid metabolism, in addition to amyloid-beta (Aβ) and tau, as major pathways in Alzheimer’s disease (AD) etiology. Accumulating evidence suggests that chronic neuroinflammation, mainly mediated by microglia and astrocytes, plays a causative role in neurodegeneration in AD. Our group and others have reported early and dramatic losses of brain sulfatide in AD cases and animal models that are mediated by ApoE in an isoform-dependent manner and accelerated by Aβ accumulation. To date, it remains unclear if changes in specific brain lipids are sufficient to drive AD-related pathology. Methods To study the consequences of CNS sulfatide deficiency and gain insights into the underlying mechanisms, we developed a novel mouse model of adult-onset myelin sulfatide deficiency, i.e., tamoxifen-inducible myelinating glia-specific cerebroside sulfotransferase (CST) conditional knockout mice (CSTfl/fl/Plp1-CreERT), took advantage of constitutive CST knockout mice (CST−/−), and generated CST/ApoE double knockout mice (CST−/−/ApoE−/−), and assessed these mice using a broad range of methodologies including lipidomics, RNA profiling, behavioral testing, PLX3397-mediated microglia depletion, mass spectrometry (MS) imaging, immunofluorescence, electron microscopy, and Western blot. Results We found that mild central nervous system (CNS) sulfatide losses within myelinating cells are sufficient to activate disease-associated microglia and astrocytes, and to increase the expression of AD risk genes (e.g., Apoe, Trem2, Cd33, and Mmp12), as well as previously established causal regulators of the immune/microglia network in late-onset AD (e.g., Tyrobp, Dock, and Fcerg1), leading to chronic AD-like neuroinflammation and mild cognitive impairment. Notably, neuroinflammation and mild cognitive impairment showed gender differences, being more pronounced in females than males. Subsequent mechanistic studies demonstrated that although CNS sulfatide losses led to ApoE upregulation, genetically-induced myelin sulfatide deficiency led to neuroinflammation independently of ApoE. These results, together with our previous studies (sulfatide deficiency in the context of AD is mediated by ApoE and accelerated by Aβ accumulation) placed both Aβ and ApoE upstream of sulfatide deficiency-induced neuroinflammation, and suggested a positive feedback loop where sulfatide losses may be amplified by increased ApoE expression. We also demonstrated that CNS sulfatide deficiency-induced astrogliosis and ApoE upregulation are not secondary to microgliosis, and that astrogliosis and microgliosis seem to be driven by activation of STAT3 and PU.1/Spi1 transcription factors, respectively. Conclusion Our results strongly suggest that sulfatide deficiency is an important contributor and driver of neuroinflammation and mild cognitive impairment in AD pathology.
In this communication, a new compact ultra‐wideband (UWB) multiple‐input multiple‐output (MIMO) antenna with band notch characteristics is presented for wireless application. It comprises of two unique monopole antenna elements sharing a similar ground plane. To reduce the coupling between antenna elements, a modified T‐shaped stub equipped with Minkowski fractal shape elements are introduced on the ground plane which in turn establish a good isolation between radiating elements. A band notch is achieved at 5.45 GHz by adding two additional rectangular stubs at 45° where symmetric slots have been etched. The efficiency and gain of the antenna drops significantly at the centre of the notch band which indicates good interference suppression. Results show that the designed antenna delivers widest impedance bandwidth (−10 dB) throughout the operating band of 3.1–20 GHz (of 146% impedance bandwidth) which covers UWB as well as Ku‐band. The antenna also produces ‐18 dB isolation for most of the operating band and ‐16 dB up to 6 GHz. The optimized antenna is fabricated and tested showing |S11| characteristics below −10 dB from 3.1 to 20 GHz band. The dimension of the proposed antenna is 18 × 26 × 1.6 mm3. Results show that the simulated characteristics are in good agreement with the measured counterpart. The designed MIMO antenna is an appropriate candidate for UWB and other wireless applications.
A novel fractal inspired antipodal Vivaldi antenna is proposed for wideband applications. A step‐by‐step procedure has been employed to design and optimise the performance of the proposed antenna. First, a conventional antipodal Vivaldi antenna (CAVA) is designed as a reference antenna and then a Koch fractal‐shaped parasitic lens is introduced in the CAVA. Finally, a fractal‐shaped dielectric lens has been added as an extension of the antenna substrate. The presence of parasitic fractal lens in the flare aperture and fractal dielectric lens enhances the antenna bandwidth and also improves field coupling between the antenna arms and produces stronger radiation in the end fire direction which in turn increases the gain and directivity of the antenna. The optimised antenna is fabricated and tested showing|S11| below −10 dB from 4.2–42 GHz band. The dimension of the proposed antenna is 186 × 66 × 1.524 mm3. Results show that |S11| characteristics and other parameters are in good agreement with the simulation counterpart.
Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilizationenabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PDlike impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached $80% after seven transplantation cycles. Transgeneexpressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.
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