Alzheimer's disease in humans and other animals; a consequence of post-reproductive lifespan and longevity rather than ageing

Research in the author’s laboratories is supported by the NIHR, MRC, ARUK, Alzheimer’s Society, Wellcome Trust and the EUIntroduction Alzheimer's disease and diabetes mellitus are linked by epidemiology, genetics, and molecular pathogenesis. They may also be linked by the remarkable observation that insulin signaling sets the limits on longevity. In worms, flies, and mice, disrupting insulin signaling increases life span leading to speculation that caloric restriction might extend life span in man. It is our contention that man is already a long-lived organism, specifically with a remarkably high postfertility life span, and that it is this that results in the prevalence of Alzheimer's disease and diabetes. Methods We review evidence for this hypothesis that carries specific predictions including that other animals with exceptionally long postreproductive life span will have increased risk of both diabetes and Alzheimer's disease. Results and Conclusions We present novel evidence that Dolphin, like man, an animal with exceptional longevity, might be one of the very few natural models of Alzheimer's disease.PostprintPeer reviewe

Fibroblasts in head neck squamous cell carcinoma associated with perineural invasion have high level nuclear Yes-Associated Protein (YAP) expression

Paul A. Reynolds, PhD, is supported by the Melville Trust for the Care and cure of Cancer.We retrospectively studied the expression of Yes-associated protein (YAP) using immunohistochemical staining in 10 cases of head and neck squamous cell carcinoma with associated perineural invasion. We find that fibroblasts in areas associated with perineural invasion show higher levels of nuclear YAP compared to fibroblasts in the stroma of normal mucosa, with a median cell count of 35.4 per high-power field in the former and 3.9 in the latter. No differences were observed between the expression of YAP phosphorylated at Ser127 in the tumoral stroma compared to that in the normal mucosa, with a median cell count expression of 4.9 in the former versus 5.0 in the latter. Therefore, a strong and increased nuclear YAP expression in fibroblasts associated with perineural invasion in head and neck squamous cell carcinoma suggests that YAP-mediated transcription programs in these fibroblasts may contribute to perineural invasion.PostprintPublisher PDFPeer reviewe

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation

This work is supported by the UK Engineering Physical Sciences Research Council (EPSRC).A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided “point-and-transfect” user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits.Publisher PDFPeer reviewe

Brain region–specific lipid alterations in the PLB4 hBACE1 knock-in mouse model of Alzheimer’s disease

We are grateful to the Alzheimer’s Society Scottish Doctoral Training Centre and the RS Macdonald Trust Transition Fund for funding the research presented.Peer reviewedPublisher PD

Spatially optimized gene transfection by laser-induced breakdown of optically trapped nanoparticles

We demonstrate laser-induced breakdown of an optically trapped nanoparticle with a nanosecond laser pulse. Controllable cavitation within a microscope sample was achieved, generating shear stress to monolayers of live cells. This efficiently permeabilize their plasma membranes. We show that this technique is an excellent tool for plasmid-DNA transfection of cells with both reduced energy requirements and reduced cell lysis compared to previously reported approaches. Simultaneous multisite targeted nanosurgery of cells is also demonstrated using a spatial light modulator for parallelizing the technique.Publisher PDFPeer reviewe

Light sheet fluorescence microscopy for neuroscience

We thank the UK Engineering and Physical Sciences Research Council for funding through grants EP/R004854/1 and EP/P030017/1.Background:  The functions of the central nervous system (CNS) rely on the interaction between large populations of neurons across different areas. Therefore, to comprehend CNS functions there is a need for imaging techniques providing access to the neuronal activity of large networks of neurons with very high spatiotemporal resolution. New method:  Light sheet fluorescence microscopy (LSFM) is a very promising optical sectioning technique that allows volumetric imaging over many length scales while retaining high spatial resolution and minimizing photobleaching and phototoxicity. Results:  The application of LSFM in neuroscience opened up the possibility of imaging in-vivo the development of the CNS and acquiring morphological images of whole cleared mammalian brains with sub-cellular resolution. The use of propagation invariant Bessel and Airy beams has shown potential for increasing the penetration depth in turbid neural tissues. Comparison with existing methods:  The lack of temporal and/or spatial resolution of traditional neuroscience imaging techniques call attention to a need for a technique capable of providing high spatio temporal resolution. LSFM, which is capable of acquiring high resolution volumetric images is increasingly becoming an interesting imaging technique for neuroscience. Conclusions:  The use of different LSFM geometries has shown the potential of this technique in acquiring in-vivo functional images of the CNS and morphological images of entire cleared mammalian brains. Further development of single objective LSFM implementations and fibre based LSFM combined with the use of propagation invariant beams could allow this technique to be used for in depth in-vivo imaging.PostprintPeer reviewe

KAJIAN KEBUTUHAN INTEGRASI LAYANAN ANGKUTAN UMUM MASSAL DI KOTA SEMARANG DAN SEKITARNYA

Angkutan umum massal berbasis jalan telah dikembangkan oleh Pemerintah Kota Semarang sejak tahun 2009 hingga kini (Trans Semarang). Disisi lain, Pemerintah Provinsi Jawa Tengah sejak tahun 2017 juga melakukan hal yang sama di Wilayah Aglomerasi Kedungsepur (Trans Jateng). Namun terkesan berjalan sendiri-sendiri dan terjadi tumpang tindih layanan di ruas-ruas jalan tertentu. Dengan demikian, perlu dilakukan penelitian kebutuhan pengintegrasian layanan angkutan umum massal di Kota Semarang dan sekitarnya. Penelitian ini menggunakan pendekatan kuantitatif dengan analisis statistik deskriptif dan analisis spasial untuk mengetahui karakteristik dan pola permintaan perjalanan penggunanya. Hasil penelitian ini menunjukkan bahwa pengguna Koridor 1 dan 2 Trans Semarang dari luar Kota Semarang mencapai 39,14% dan 60,86% berasal dari dalam Kota Semarang. Pengguna dengan tujuan ke luar Kota Semarang mencapai 42,23% dan 57,77% tujuan di dalam Kota Semarang. Hal ini membuktikan bahwa Koridor 1 dan 2 mengakomodasi penumpang yang asal tujuannya cukup besar dari luar Kota Semarang. Terdapat tumpang tindih layanan mencapai 60% dari panjang lintasan di Koridor 1 Trans Jateng dan Koridor 2 Trans Semarang. Moda first mile pengguna Koridor 2 didominasi oleh Trans Jateng sebesar 51,51% dan last mile didominasi oleh penggunaan motor sebesar 48,10%. Penelitian ini menyarankan bahwa rute layanan Trans Jateng kedepannya dapat mengakomodir permintaan perjalanan di dalam kawasan penyangga dengan konsep layanan loop (mengelilingi), berbeda dari kondisi saat ini. Selanjutnya, layanan Trans Jateng yang menuju ke Kota Semarang dapat berhenti di titik perbatasan, dimana pergerakan kemudian dilayani oleh Trans Semarang dan diharapkan dapat memberikan layanan yang lebih baik kepada masyarakat di Kota Semarang dan sekitarnya.

Is Amyloid Binding Alcohol Dehydrogenase a Drug Target for Treating Alzheimer's Disease?

Current strategies for the treatment of Alzheimer's disease (AD) involve tackling the formation or clearance of the amyloid-beta peptide (Aβ) and/or hyper-phosphorylated tau, or the support and stabilization of the remaining neuronal networks. However, as we gain a clearer idea of the large number of molecular mechanisms at work in this disease, it is becoming clearer that the treatment of AD should take a combined approach of dealing with several aspects of the pathology. The concept that we also need to protect specific sensitive targets within the cell should also be considered. In particular the role of protecting the function of a specific mitochondrial protein, amyloid binding alcohol dehydrogenase (ABAD), will be the focus of this review. Mitochondrial dysfunction is a well-recognized fact in the progression of AD, though until recently the mechanisms involved could only be loosely labeled as changes in `metabolism'. The discovery that Aβ can be present within the mitochondria and specifically bind to ABAD, has opened up a new area of AD research. Here we review the evidence that the prevention of Aβ binding to ABAD is a drug target for the treatment of AD

Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function

Authors would like to acknowledge ARUK for supporting this research. YC is Chinese Scholarship recipient. The University of St Andrews is a charity registered in Scotland: No SC013532Mitochondrial dysfunction has a recognised role in the progression of Alzheimer's disease (AD) pathophysiology. Cerebral perfusion becomes increasingly inefficient throughout ageing, leading to unbalanced mitochondrial dynamics. This effect is exaggerated by amyloid β (Aβ) and phosphorylated tau, two hallmark proteins of AD pathology. A neuroprotective role for the adipose‐derived hormone, leptin, has been demonstrated in neuronal cells. However, its effects with relation to mitochondrial function in AD remain largely unknown. To address this question, we have used both a glucose‐serum deprived (CGSD) model of ischaemic stroke in SH‐SY5Y cells and a Aβ1‐42‐treatment model of AD in differentiated hippocampal cells. Using a combination of JC‐1 and MitoRed staining techniques, we show that leptin prevents depolarisation of the mitochondrial membrane and excessive mitochondrial fragmentation induced by both CGSD and Aβ1‐42. Thereafter, we used ELISAs and a number of activity assays to reveal the biochemical underpinnings of these processes. Specifically, leptin was seen to inhibit upregulation of the mitochondrial fission protein Fis1 and downregulation of the mitochondrial fusion protein, Mfn2. Furthermore, leptin was seen to upregulate the expression and activity of the antioxidant enzyme, monoamine oxidase B. Herein we provide the first demonstration that leptin is sufficient to protect against aberrant mitochondrial dynamics and resulting loss of function induced by both CGSD and Aβ1‐42. We conclude that the established neuroprotective actions of leptin may be facilitated through regulation of mitochondrial dynamics.Publisher PDFPeer reviewe