A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-01-12, accepted 2021-04-22, epub 2021-05-20Publication status: PublishedIntroduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD

Glucose transporters in Alzheimer's disease

BACKGROUND: Physiological brain function depends on tight glucose regulation, including transport and phosphorylation, the first step in its metabolism. Impaired glucose regulation is increasingly implicated in the pathophysiology of Alzheimer's disease (AD). Glucose hypometabolism in AD may be at least partly due to impaired glucose transport at the blood-brain barrier (BBB). Glucose transporters (GLUTs) are an integral component of the BBB. There is evidence of a significant reduction in vascular and non-vascular forms of GLUT1 and GLUT3 in AD brains compared to age-matched controls. Glucose transport, as well as phosphorylation, appears to be a rate limiting step for glucose metabolism in the brain. We have reviewed the literature on glucose transport abnormalities in AD and the effect such abnormalities have on the brain. METHOD: Published literature between 1st January 1946 and 1st November 2019 was identified using EMBASE and MEDLINE databases and titles and abstracts were scanned. Human studies (autopsy and imaging) and data from animal models were included while reviews, letters and cellular or molecular studies were excluded from the search. RESULT: Autopsy studies in AD patients show significant reductions in GLUT3 in areas of the brain closely associated with AD pathology. Patients with AD and diabetes showed greater reductions of GLUT1 and GLUT3. A longitudinal study showed significant reductions in GLUT3 levels which correlated with greater amyloid-β (Aβ) and neurofibrillary tangle pathological burden in participants with AD pathology at post-mortem but without evidence of cognitive dysfunction in their lifetime. Some studies showed increased GLUT1, with others showing reduced GLUT1, levels in AD brain. A newly recognised GLUT12 appears to be increased in AD. Animal studies showed similar results with GLUT1 and GLUT3 knockout animal models exhibiting AD pathology, while overexpression of GLUT1 or treatment with metformin decreased Aβ toxicity in a Drosophila model of AD. GLUT2 levels were increased in both human AD brain and in an animal model of AD. Imaging studies using fluorodeoxyglucose [18F]FDG with positron emission tomography (FDG-PET) in AD subjects show reductions in glucose transport and glucose metabolism in areas most affected in AD. A small randomised control trial showed anti-diabetic medications improved the glucose transport in AD subjects. CONCLUSION: GLUTs play a significant role in AD pathology with evidence suggesting that GLUT3 reductions may precede the onset of clinical symptoms, while GLUT2 and GLUT12 may have a compensatory role. Repurposing anti-diabetic drugs shows promising results in both animal and human studies of AD

Ethics and (Inter-)Professionalism in Health Care at the End of Life:A Position Paper

This position paper summarizes key results from the workshop “Professional Ethics at the End of Life” held from 27 May to 1 June 2019 in Greifswald (Germany). An international group of 13 young scholars from six countries and various healthcare-related disciplines (e.g. nursing, medicine, philosophy, theology, gerontology, psychology) met to discuss ethical issues in patient care at the end of life. A special focus of the workshop was on international comparisons and the roles and moral obligations of health-care professionals. The need for interprofessional dialogue and family involvement emerged as key factors for patient-centred, holistic care at the end of life. Further main results were collected from the participants subsequent to the workshop, arranged regarding content and further circulated and revised within the group. The position paper, therefore, represents the views of young health-care researchers and practitioners with respect to the current status and further perspectives of professionalism and interprofessional care at the end of life. It can serve as a starting point for scientific and political debates on moral obligations, professional practice and health-care structures