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      Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer’s disease

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          Abstract

          Several studies support the relation between leptin and Alzheimer’s disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Aβ 1-42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Aβ accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time.

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          Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.

          Michael W. Schwartz, Elaine R. Peskind, Murray Raskind … (1996)
          The adipocyte hormone, leptin (OB protein), is proposed to be an "adiposity signal" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.
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            Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging.

            Wolfgang Lieb, Alexa S Beiser, Ramachandran S Vasan … (2009)
            The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. Incidence of dementia and AD during follow-up until December 31, 2007. During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.
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              Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.

              Yun Zhou, Martin Broadstock, Gerome Breen … (2010)
              Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging Cell
                Journal ID (iso-abbrev): Aging Cell
                Journal ID (publisher-id): acel
                Title: Aging Cell
                Publisher: BlackWell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1474-9718
                ISSN (Electronic): 1474-9726
                Publication date (Print): February 2015
                Publication date (Electronic): 02 December 2014
                Volume: 14
                Issue: 1
                Pages: 122-129
                Affiliations
                [1 ]Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics Stockholm, Sweden
                [2 ]Karolinska Institutet Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Division for clinical geriatrics Stockholm, Sweden
                [3 ]Institute of Psychiatry, King’s College London London, UK
                [4 ]Medical and Surgical Science, Department-DIMEC-University of Bologna Bologna, Italy
                [5 ]Department of Pharmacology and Toxicology, University of Navarra Pamplona, Spain
                [6 ]NIHR Biomedical Research, Centre for Mental Health, King’s College London London, UK
                [7 ]NIHR Biomedical Research, Unit for Dementia, King’s College London London, UK
                [8 ]Department of Cellular and Molecular Neuropharmacology, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra Pamplona, Spain
                Author notes
                Correspondence, Angel Cedazo-Minguez and Silvia Maioli, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, 141 57 Stockholm, Sweden. Tel.: +46 8 585 83751; fax: +46 8 585 83880; e-mails : Angel.Cedazo-Minguez@ 123456ki.se ; silvia.maioli@ 123456ki.se
                [*]

                Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

                Article
                DOI: 10.1111/acel.12281
                PMC ID: 4326905
                PubMed ID: 25453257
                SO-VID: ecf46a74-d979-443f-bb6b-0dcdb35509f5
                Copyright © © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 24 September 2014
                Categories
                Subject: Original Articles

                ScienceOpen disciplines: Cell biology
                Keywords: alzheimer’s disease,amyloid-beta,apoe genotype,csf,leptin receptors,leptin
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: alzheimer’s disease, amyloid-beta, apoe genotype, csf, leptin receptors, leptin

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