Obesity‐related leptin regulates Alzheimer's Aβ

Fewlass, Darius C; Noboa, Karina; Pi‐Sunyer, F. Xavier; Johnston, Jane M.; Yan, Shi Du; Tezapsidis, Nikolaos

doi:10.1096/fj.04-2572com

Cited by 283 publications

(258 citation statements)

References 52 publications

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“…Leptin also directly interferes with the accumulation of Ab, as leptin is reported to inhibit b-secretase activity, thereby reducing production of Ab [71]. In addition, cytoplasmic Ab levels are lowered by leptin, as neuronal uptake of Ab is increased in the presence of leptin [71]. Another key pathological hallmark of AD is neurofibrillary tangles comprising hyperphosphorylated tau.…”

Section: Leptin Prevents Synaptic Disruption and Neuronal Cell Deathmentioning

confidence: 99%

Leptin regulation of hippocampal synaptic function in health and disease

Irving

Harvey

2014

Phil. Trans. R. Soc. B

102

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The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

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Section: Leptin Prevents Synaptic Disruption and Neuronal Cell Deathmentioning

confidence: 99%

Leptin regulation of hippocampal synaptic function in health and disease

Irving

Harvey

2014

Phil. Trans. R. Soc. B

102

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“…Besides this pleiotropic role, leptin has shown to promote beneficial effects on memory, including enhancement of long-term potentiation with consequent cognitive improvement when directly administered on dentate gyrus or CA1 hippocampal region (Shanley et al 2001;Wayner et al 2004) and also to influence hippocampal synaptic plasticity by enhancing N-methyl-D-aspartate (NMDA) receptors (Durakoglugil et al 2005). Data from cell cultures and AD animal models show evidence of the role of this adipocytokine in amyloid precursor protein (APP) metabolism, namely a reduction of amyloid-beta (Aβ) peptide production by blocking β-secretase activity and increasing Apolipoprotein E (ApoE) dependent Aβ uptake (Fewlass et al 2004). Moreover, leptin seems to promote phosphorylation (and deactivation) of glycogen synthase kinase beta (GSK-3β), the main responsible for abnormal tau phosphorylation (Greco et al 2009).…”

Section: Leptinmentioning

confidence: 99%

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

2014

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Alzheimer's disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood-brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer's diseasetransgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent betaamyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with midlife obesity, unraveling its insulin-independent effects on cognition.

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“…Reduced brain weight, myelinization and synaptogenesis, the indicators of impaired CNS development and predictors of neurological ailments, have been reported in congenital leptindeficient humans and rodents [1,16,24,49,50,95,100,108,117,128]. Intriguingly, leptin insufficiency in the brain of obese and diabetic patients, may also adversely impact neural functions [2,38,49,50,58,60].…”

Section: Impaired Brain Development and Cognitive Functionmentioning

confidence: 99%

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

Kalra

2008

Peptides

117

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This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally-imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a sitespecific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequalae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.

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Obesity‐related leptin regulates Alzheimer's Aβ

Cited by 283 publications

References 52 publications

Leptin regulation of hippocampal synaptic function in health and disease

Leptin regulation of hippocampal synaptic function in health and disease

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

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