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Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

ABSTRACT: Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-?. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.

SUBMITTER: Bonda DJ

PROVIDER: S-EPMC3867585 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

Bonda David J DJ Stone Jeremy G JG Torres Sandy L SL Siedlak Sandra L SL Perry George G Kryscio Richard R Jicha Gregory G Casadesus Gemma G Smith Mark A MA Zhu Xiongwei X Lee Hyoung-Gon HG

Journal of neurochemistry 20130821 1

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin r ...[more]

PMID: 23895348

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Project description:To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.Validation sample.Multisite, referral centers.A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the A?42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.Three AD biomarkers (ie, the CSF A?42 level, the CSF total tau level, and the adjusted hippocampal volume).Within each clinical group of the entire sample (n = 401), the CSF A?42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal A?42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF A?42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.A reduction in the CSF A?42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

Dataset Information

Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

Publications

Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

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