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-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 receptor in AD and control patients. We analyzed leptin levels in cerebrospinal fluid (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 to age-matched control cases, indicate a physiological upregulation 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.

Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease

“…If so, since leptin plays a key role in the developing brain (Steppan and Swick, 1999;Stieg et al, 2015;Farr et al, 2014;Bouret, 2010;Johnston et al, 2014;Pérez-González et al, 2011;Busch et al, 2011;Folch et al, 2012;Zhang et al, 2013;Mancini et al, 2014;Davis et al, 2014) are the high leptin concentrations in serum associated with high CSF leptin and low leptin receptors mRNA in target areas like hippocampus as in Alzheimer's patients? (Bonda et al, 2014a(Bonda et al, , 2014b. If indeed, aberrant leptin signaling is present in urban children as in patients with neuroinflammatory entities, i.e., AIDS and Alzheimer's disease (Bonda et al, 2014a(Bonda et al, , 2014bHuang et al, 2007;Johnston et al, 2014) will children's brain development be compromised?…”

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

“…In fact, despite peripheral hyperproduction of leptin in obese individuals, brain resistance to its action will also develop. Bonda et al (2014) demonstrated recently that besides up-regulation of leptin in AD patients' CSF and hippocampus, leptin receptor mRNA was decreased in the brain tissue and its protein was localized to neurofibrillary tangles. Interestingly, leptin CSF levels showed a positive relation with the Braak staging (plaque and tangle distribution at different stages of Alzheimer's disease progression) and were independent of age and BMI.…”

Clinicotherapeutic Potential of Leptin in Alzheimer’s Disease and Parkinson’s Disease

“…Accumulation of amyloid beta (A ) and tau hyperphosphorylation within the CNS are implicated significantly in the pathogenesis of neurodegenerative diseases like AD and PD [30][31][32], and leptin affects these two vital processes [33]. Dysregulation of leptin signaling pathway and neuronal leptin resistance have been recently shown to underlie the pathophysiology of AD [33].…”

“…Dysregulation of leptin signaling pathway and neuronal leptin resistance have been recently shown to underlie the pathophysiology of AD [33]. Ob-Rb trafficking to the cell membrane depends on proper functioning of microtubules, and tau protein is a microtubule associated protein [34,35].…”

“…Ob-Rb trafficking to the cell membrane depends on proper functioning of microtubules, and tau protein is a microtubule associated protein [34,35]. Findings by Bonda et al suggest that, due to formation of neurofibrillary tangles (NFTs) by hyperphosphorylated tau proteins, the Ob-Rb leptin receptors cannot translocate to the neuronal cell membranes but get sequestered in the NFTs, thereby causing physical inaccessibility of leptin to its receptors [33]. The resultant decline of leptin signaling causes hypersecretion of leptin and hence its level in circulation increases under such circumstances [36].…”