Alzheimer's disease (AD) is associated with early metabolic dysfunction and adiponectin, which may play a pathophysiological role. Adiponectin is implicated in the regulation of energy homeostasis, carbohydrate, and lipid metabolism, as well as in inflammation modulation. The aim of this study was to study whether plasma adiponectin levels were different between patients with AD confirmed by biomarkers and neurological control subjects. We performed a monocentric, retrospective, cross-sectional, observational study in AD patients and neurological controls recruited from daily clinical practice in a tertiary memory clinic. Plasma adiponectin levels were measured using a chemiluminescent enzyme immunoassay. We analyzed the relationship between adiponectin and AD using linear regression models including age, gender, and BMI. We also described the distribution of adiponectin concentrations, across age, and gender categories. Two hundred and six patients (142 AD patients and 64 neurological controls) were included, with mean age = 68.8 ± 10.0 years, and 56% were women. Higher adiponectin concentrations were observed in females and in older adults. Plasma adiponectin levels were significantly higher in AD patients (mean = 6.45 ± 3.42 μg/mL) than neurological controls (4.85 ± 3.54 μg/mL) (p < .001). This association was mediated by age, gender, and BMI, which were significantly and independently associated with plasma adiponectin levels (p < .01 for each), while adiponectin was no longer associated with AD in multivariate models. Patients with AD showed higher adiponectin levels, but this association was driven by older age, female gender, and lower BMI in the AD group. Further studies are needed to better characterize the hormonal signature of AD.

Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.

The complex pathophysiology of Alzheimer's disease (AD) poses challenges for the development of therapies. Recently, neuroinflammation has been identified as a key pathogenic mechanism underlying AD, while inflammation has emerged as a possible target for the management and prevention of AD. Several prior studies have demonstrated that medications modulating neuroinflammation might lessen AD symptoms, mostly by controlling neuroinflammatory signaling pathways such as the NF-κB, MAPK, NLRP3, etc, and their respective signaling cascade. Moreover, targeting these inflammatory modalities with inhibitors, natural products, and metabolites has been the subject of intensive research because of their anti-inflammatory characteristics, with many studies demonstrating noteworthy pharmacological capabilities and potential clinical applications. Therefore, targeting inflammation is considered a promising strategy for treating AD. This review comprehensively elucidates the neuroinflammatory mechanisms underlying AD progression and the beneficial effects of inhibitors, natural products, and metabolites in AD treatment.

Aging is the main risk factor for developing cognitive impairments and associated neurodegenerative diseases. However, environmental factors, including nutritional health, are likely to promote or reduce cognitive impairments and neurodegenerative pathologies. An intricate relationship exists between maternal nutrition and adult eating behavior, metabolic phenotype, and cognitive abilities.

The objective of the present review was to collect available data, suggesting a link between maternal overnutrition and the latter impairment of cognitive functions in the progeny, and to relate this relationship with Alzheimer's disease (AD). Indeed, cognitive impairments are major behavioral signs of AD. We first reviewed studies showing an association between unbalanced maternal diet and cognitive impairments in the progeny in humans and rodent models. Then we looked for cellular and molecular hallmarks which could constitute a breeding ground for AD in those models. With this end, we focused on synaptic dysfunction, altered neurogenesis, neuroinflammation, oxidative stress, and pathological protein aggregation. Finally, we proposed an indirect mechanism linking maternal unbalanced diet and progeny's vulnerability to cognitive impairments and neurodegeneration through promoting metabolic diseases. We also discussed the involvement of progeny's gut microbiota in the maternal diet-induced vulnerability to metabolic and neurodegenerative diseases.

Further investigations are needed to fully decipher how maternal diet programs the fetus and infant brain. Addressing this knowledge gap would pave the way to precise nutrition and personalized medicine to better handle cognitive impairments in adulthood.

Leptin is a hormone produced from adipose tissue, targeting the hypothalamus and regulating energy expenditure, adipose tissue mass, and reproductive function. Leptin concentration reflects body weight and the amount of energy stored, as well as the level of reproductive hormones and male fertility. In this review, the aim was to focus on leptin signaling mechanisms and the significant influence of leptin on the male reproductive system and to summarize the current knowledge of clinical and experimental studies. The PubMed database was searched for studies on leptin and the male reproductive system to summarize the mechanism of leptin in the male reproductive system. Studies have shown that obesity-related, high leptin levels or leptin resistance negatively affects male reproductive functions. Leptin directly affects the testis by binding to the hypothalamic-pituitary-gonadal axis and the receptors of testicular cells, and thus the location of leptin receptors plays a key role in the regulation of the male reproductive system with the negative feedback mechanism between adipose tissue and hypothalamus. Based on the current evidence, leptin may totally inhibit male reproduction, and investigation of this role of leptin has established a potential interaction between obesity and male infertility. The mechanism of leptin in the male reproductive system should be further investigated and possible treatments for subfertility should be evaluated, supported by better understanding of leptin and associated signaling mechanisms.

Neurodegeneration is preeminent in many neurological diseases, and still a major burden we fail to manage in patient's care. Its pathogenesis is complicated, intricate, and far from being completely understood. Taking multiple sclerosis as an example, we propose that neurodegeneration is neither a cause nor a consequence by itself. Mitochondrial dysfunction, leading to energy deficiency and ion imbalance, plays a key role in neurodegeneration, and is partly caused by the oxidative stress generated by microglia and astrocytes. Nodal and paranodal disruption, with or without myelin alteration, is further involved. Myelin loss exposes the axons directly to the inflammatory and oxidative environment. Moreover, oligodendrocytes provide a singular metabolic and trophic support to axons, but do not emerge unscathed from the pathological events, by primary myelin defects and cell apoptosis or secondary to neuroinflammation or axonal damage. Hereby, trophic failure might be an overlooked contributor to neurodegeneration. Thus, a complex interplay between neuroinflammation, demyelination, and neurodegeneration, wherein each is primarily and secondarily involved, might offer a more comprehensive understanding of the pathogenesis and help establishing novel therapeutic strategies for many neurological diseases and beyond.

Leptin, a hormone secreted by adipose tissue, plays a pivotal role in maintaining energy metabolism and bone quality. Dysregulation of leptin can lead to the development of various pathological conditions. For example, the concentration of leptin is increased in individuals with obesity, and this increased concentration is positively correlated with higher bone mass. In addition, mice lacking leptin or the leptin receptor exhibit substantial bone loss, further highlighting the pivotal role of leptin in regulating bone metabolism. However, the precise mechanism through which leptin affects bone remodeling remains unclear. The present study investigated the effect of leptin on osteoclastogenesis and osteoblastogenesis. Osteoblasts derived from MC3T3-E1 cells and osteoclasts derived from RAW 264.7 cells were used. The findings revealed that leptin did not substantially affect osteoclastogenesis or osteoblastogenesis. Furthermore, leptin did not affect cell viability during osteoclast differentiation. The expression of inflammatory mediators was increased in differentiating RAW 264.7 cells. However, the expression of critical bone resorptive genes, including Ctsk and tartrate-resistant acid phosphatase, was not elevated following leptin stimulation. By contrast, leptin did not alter the expression of key osteogenic genes in preosteoblasts in the early stage of differentiation. These data demonstrate that leptin can stimulate the expression of pro-inflammatory mediators in differentiating osteoclasts. These changes do not affect osteoblastogenesis or osteoclastogenesis. Leptin may downregulate bone resorption and enhance mineralization to increase bone mass.

We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults.

We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols.

Higher sOB-R was associated with lower fractional anisotropy (FA, β = -0.114 ± 0.02, p < 0.001), and higher free water (FW, β = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, β = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (β = 0.115 ± 0.027, p < 0.001) and lower FW (β = -0.096 ± 0.029, p = 0.001) and PSMD (β = -0.085 ± 0.028, p = 0.002).

Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk.

Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

The progression of Alzheimer's disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer's disease. This study, in using an amyloid overexpression AppNL-G-F mouse model under normal metabolic conditions, examines blood markers in young and old male AppNL-G-F mice (n = 5) that corresponds to the silent and active phases of AD, and bulk gene expression changes in the hypothalamus and the hippocampus. The results show a large panel of inflammatory mediators, leptin, and other proteins that may be involved in weakening the blood brain barrier, to be increased in the young AppNL-G-F mice but not in the old AppNL-G-F mice. There were also several differentially expressed genes in both the hypothalamus and the hippocampus in the young AppNL-G-F mice prior to amyloid plaque formation and cognitive decline that persisted in the old AppNL-G-F mice, including GABRa2 receptor, Wdfy1, and several pseudogenes with unknown function. These results suggests that a larger panel of inflammatory mediators may be used as blood markers to detect silent AD, and that a change in leptin and gene expression in the hypothalamus exist prior to cognitive effects, suggesting a coupling of metabolism with amyloid plaque induced cognitive decline.

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aβ, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Air pollution is an urgent concern linked to numerous health problems in low- and middle-income countries, where 92% of air pollution-related deaths occur. Particulate matter 2.5 (PM2.5) is the most harmful component of air pollutants, increasing inflammation and changing gut microbiota, favoring obesity, type 2 diabetes, and Alzheimer's Disease (AD). PM2.5 contains lipopolysaccharides (LPS), which can activate the Toll-like receptor 4 (TLR4) signaling pathway. This pathway can lead to the release of pro-inflammatory markers, including interleukins, and suppressor of cytokine signaling-3 (SOCS3), which inhibits leptin action, a hormone that keeps the energy homeostasis. Leptin plays a role in preventing amyloid plaque deposition and hyperphosphorylation of tau-protein (p-tau), mechanisms involved in the neurodegeneration in AD. Approximately 50 million people worldwide are affected by dementia, with a significant proportion living in low-and middle-income countries. This number is expected to triple by 2050. This mini-review focuses on the potential impact of PM2.5 exposure on the TLR4 signaling pathway, its contribution to leptin resistance, and dysbiosis that exacerbates the link between obesity and AD.

Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful.

In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics.

Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release.

The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature.

A growing body of evidence suggests that cardiometabolic risk factors play a significant role in Alzheimer's disease (AD). Diabetes, obesity and hypertension are highly prevalent and can accelerate neurodegeneration and perpetuate the burden of AD. Insulin resistance and enzymes including insulin degrading enzymes are implicated in AD where breakdown of insulin is prioritised over amyloid-β. Leptin resistance and inflammation demonstrated by higher plasma and central nervous system levels of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-α, are mechanisms connecting obesity and diabetes with AD. Leptin has been shown to ameliorate AD pathology and enhance long-term potentiation and hippocampal-dependent cognitive function. The renin-aldosterone angiotensin system, involved in hypertension, has been associated with AD pathology and neurotoxic reactive oxygen species, where angiotensin binds to specific angiotensin-1 receptors in the hippocampus and cerebral cortex. This review aims to consolidate the evidence behind putative processes stimulated by obesity, diabetes and hypertension, which leads to increased AD risk. We focus on how novel knowledge can be applied clinically to facilitate recognition of efficacious treatment strategies for AD.

Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood.

To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults.

This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included.

Plasma leptin levels as assessed by enzyme-linked immunosorbent assay.

Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans.

Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27).

The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Mitochondria are the powerhouse of the cell. Mitochondria serve as the major source of oxidative stress. Impaired mitochondria produce less adenosine triphosphate (ATP) but generate more reactive oxygen species (ROS), which could be a major factor in the oxidative imbalance observed in Alzheimer's disease (AD). Well-balanced mitochondrial respiration is important for the proper functioning of cells and human health. Indeed, recent research has shown that elevated mitochondrial respiration underlies the development and therapy resistance of many types of cancer, whereas diminished mitochondrial respiration is linked to the pathogenesis of AD. Mitochondria govern several activities that are known to be changed in lung cancer, the largest cause of cancer-related mortality worldwide. Because of the significant dependence of lung cancer cells on mitochondrial respiration, numerous studies demonstrated that blocking mitochondrial activity is a potent strategy to treat lung cancer. Heme is a central factor in mitochondrial respiration/oxidative phosphorylation (OXPHOS), and its association with cancer is the subject of increased research in recent years. In neural cells, heme is a key component in mitochondrial respiration and the production of ATP. Here, we review the role of impaired heme metabolism in the etiology of AD. We discuss the numerous mitochondrial effects that may contribute to AD and cancer. In addition to emphasizing the significance of heme in the development of both AD and cancer, this review also identifies some possible biological connections between the development of the two diseases. This review explores shared biological mechanisms (Pin1, Wnt, and p53 signaling) in cancer and AD. In cancer, these mechanisms drive cell proliferation and tumorigenic functions, while in AD, they lead to cell death. Understanding these mechanisms may help advance treatments for both conditions. This review discusses precise information regarding common risk factors, such as aging, obesity, diabetes, and tobacco usage.

Adiponectin is an adipokine playing a central role in the regulation of energy homeostasis, carbohydrate and lipid metabolism, as well as immunomodulation. The relationship between Alzheimer's disease (AD) and body composition has highlighted the bidirectional crosstalk between AD's pathophysiology and metabolic disorders. This review aimed to report the current state of knowledge about cellular and molecular mechanisms linking adiponectin and AD, in preclinical studies. Then, we reviewed human studies to assess the relationship between adiponectin levels and AD diagnosis. We also examined the risk of incident AD regarding the participants' baseline adiponectin level, as well as the relationship of adiponectin and cognitive decline in patients with AD. We conducted a systematic review, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, of studies published over the last decade on MEDLINE and Cochrane databases. Overall, we reviewed 34 original works about adiponectin in AD, including 11 preclinical studies, two both preclinical and human studies and 21 human studies. Preclinical studies brought convincing evidence for the neuroprotective role of adiponectin on several key mechanisms of AD. Human studies showed conflicting results regarding the relationship between AD and adiponectin levels, as well as regarding the cross-sectional association between cognitive function and adiponectin levels. Adiponectin did not appear as a predictor of incident AD, nor as a predictor of cognitive decline in patients with AD. Despite solid preclinical evidence suggesting the protective role of adiponectin in AD, inconsistent results in humans supports the need for further research.

Obesity is a global epidemic, affecting roughly 30% of the world's population and predicted to rise. This disease results from genetic, behavioral, societal, and environmental factors, leading to excessive fat accumulation, due to insufficient energy expenditure. The adipose tissue, once seen as a simple storage depot, is now recognized as a complex organ with various functions, including hormone regulation and modulation of metabolism, inflammation, and homeostasis. Obesity is associated with a low-grade inflammatory state and has been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). Mechanistically, reduced adipose expandability leads to hypertrophic adipocytes, triggering inflammation, insulin and leptin resistance, blood-brain barrier disruption, altered brain metabolism, neuronal inflammation, brain atrophy, and cognitive decline. Obesity impacts neurodegenerative disorders through shared underlying mechanisms, underscoring its potential as a modifiable risk factor for these diseases. Nevertheless, further research is needed to fully grasp the intricate connections between obesity and neurodegeneration. Collaborative efforts in this field hold promise for innovative strategies to address this complex relationship and develop effective prevention and treatment methods, which also includes specific diets and physical activities, ultimately improving quality of life and health.

Amyloid-β (Aβ) and hyper-phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis-localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau-driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto-toxic effects of tau may prevent AD-related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ-induced toxicity. However, it is unclear if leptin protects against tau-related synaptic dysfunction. Here we show that Aβ1-42 significantly increases dendritic and synaptic levels of tau and p-tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK-3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3-kinase (PI3K) activation and inhibition of GSK-3β. Aβ1-42 -driven synaptic targeting of tau was associated with the removal of GluA1-containing AMPARs from synapses, which was also inhibited by leptin-driven inhibition of GSK-3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1-containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity-dependent long-term potentiation (LTP) at hippocampal SC-CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre-clinical stages of AD and further validate the leptin system as a therapeutic target in AD.

Microglia are closely linked to Alzheimer's disease (AD) many years ago; however, the pathological mechanisms of AD remain unclear. The purpose of this study was to determine whether leptin affected microglia in the hippocampus of young and aged male APP/PS1 mice.

In a transgenic model of AD, we investigated the association between intraperitoneal injection of leptin and microglia.

We intraperitoneal injection of leptin (1mg/kg) every day for one week and analyzed inflammatory markers in microglia in the hippocampus of adult (6 months) and aged (12 months) APP/PS1 mice.

In all leptin treatment group, the brain Aβ levels were decrease. We found increased levels of IL-1β, IL-6 and microglial activation in the hippocampus of adult mice. Using aged mice as an experimental model for chronic neuroinflammation and leptin resistance, the number of Iba-1+ microglia and the levels of IL-1β/IL-6 in the hippocampus were greatly increased as compared to the adult. But between the leptin treatment and un-treatment, there were no difference.

Leptin signaling would regulate the activation of microglia and the release of inflammatory factors, but it is not the only underlying mechanism in the neuroprotective effects of AD pathogenesis.

Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.

Alzheimer's disease (AD) represents a significant public health concern in modern society. Metabolic syndrome (MetS), which includes diabetes mellitus (DM) and obesity, represents a modifiable risk factor for AD. MetS and AD are interconnected through various mechanisms, such as mitochondrial dysfunction, oxidative stress, insulin resistance (IR), vascular impairment, inflammation, and endoplasmic reticulum (ER) stress. Therefore, it is necessary to seek a multi-targeted and safer approach to intervention. Thus, 10-hydroxy-2-decenoic acid (10-HDA), a unique hydroxy fatty acid in royal jelly, has shown promising anti-neuroinflammatory, blood-brain barrier (BBB)-preserving, and neurogenesis-promoting properties. In this paper, we provide a summary of the relationship between MetS and AD, together with an introduction to 10-HDA as a potential intervention nutrient. In addition, molecular docking is performed to explore the metabolic tuning properties of 10-HDA with associated macromolecules such as GLP-1R, PPARs, GSK-3, and TREM2. In conclusion, there is a close relationship between AD and MetS, and 10-HDA shows potential as a beneficial nutritional intervention for both AD and MetS.

Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by several pathological features. In AD and PD, there is an abnormal accumulation of toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, increased astrocyte activation, and perhaps a state of insulin resistance. Epidemiological evidence has revealed a link between AD/PD and type 2 diabetes mellitus, with these disorders sharing some pathological commonalities. Such a link has opened up a promising avenue for repurposing antidiabetic agents in the treatment of neurodegenerative disorders. A successful therapeutic strategy for AD/PD would likely require a single or several agents which target the separate pathological processes in the disease. Targeting cerebral insulin signalling produces numerous neuroprotective effects in preclinical AD/PD brain models. Clinical trials have shown the promise of approved diabetic compounds in improving motor symptoms of PD and preventing neurodegenerative decline, with numerous further phase II trials and phase III trials underway in AD and PD populations. Alongside insulin signalling, targeting incretin receptors in the brain represents one of the most promising strategies for repurposing currently available agents for the treatment of AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists have displayed impressive clinical potential in preclinical and early clinical studies. In AD the GLP-1 receptor agonist, liraglutide, has been demonstrated to improve cerebral glucose metabolism and functional connectivity in small-scale pilot trials. Whilst in PD, the GLP-1 receptor agonist exenatide is effective in restoring motor function and cognition. Targeting brain incretin receptors reduces inflammation, inhibits apoptosis, prevents toxic protein aggregation, enhances long-term potentiation and autophagy as well as restores dysfunctional insulin signalling. Support is also increasing for the use of additional approved diabetic treatments, including intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear receptor γ agonists, amylin analogs, and protein tyrosine phosphatase 1B inhibitors which are in the investigation for deployment in PD and AD treatment. As such, we provide a comprehensive review of several promising anti-diabetic agents for the treatment of AD and PD.

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure-activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.

Determining whether changes in leptin signaling plays a role in the improvement of cognitive function post-bariatric surgery may aid in the understanding and development of novel therapeutic approaches targeting cognitive dysfunction through the greater understanding of processes connecting obesity and brain health. Several studies have explored the effects of cognition post bariatric surgery, and others have studied leptin and its changes post surgery. However the amalgamation of the effects of leptin signaling in relation to cognition post bariatric surgery have yet to be considered as key tools in the understanding of cognitive dysfunction in obese subjects with leptin resistance or insensitivity. This review serves to highlight the potential correlations, to further elucidate the effect of improved leptin signaling on cognition post bariatric surgery, and to propose a direct cause for the improvement of cognitive function via the amelioration of the leptin Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathway as a result of the reversal of inflammatory processes involved in diseased individuals.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear.

We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin.

A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD.

After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance.

Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.

An increasing body of experimental evidence implicates a relationship between immunometabolic deterioration and the progression of Parkinson's disease (PD) with a dysregulation of central and peripheral neuroinflammatory networks mediated by circulating adipokines, in particular leptin. We screened the current literature on the role of adipokines in PD. Hence, we searched known databases (PubMed, MEDLINE/OVID) and reviewed original and review articles using the following terms: "leptin/ObR", "Parkinson's disease", "immune-metabolism", "biomarkers" and "neuroinflammation". Focusing on leptin, we summarize and discuss the existing in vivo and in vitro evidence on how adipokines may be protective against neurodegeneration, but at the same time contribute to the progression of PD. These components of the adipose brain axis represent a hitherto underestimated pathway to study systemic influences on dopaminergic degeneration. In addition, we give a comprehensive update on the potential of adjunctive therapeutics in PD targeting leptin, leptin-receptors, and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanisms of action and the value of central and peripheral adipose-immune-metabolism molecular phenotyping in order to develop and validate the differential roles of different adipokines as potential therapeutic target for PD patients.

Diabetes is among the most prevalent diseases of the modern world and is strongly linked to an increased risk of numerous neurodegenerative disorders, although the exact pathophysiological mechanisms are not clear yet. Insulin resistance is a serious pathological condition, connecting type 2 diabetes, metabolic syndrome, and obesity. Recently, insulin resistance has been proven to be connected also to cognitive decline and dementias, including the most prevalent form, Alzheimer's disease. The relationship between diabetes and Alzheimer's disease regarding pathophysiology is so significant that it has been proposed that some presentations of the condition could be termed type 3 diabetes.

Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.

Metabolic dysfunction links to cognitive deficits in Alzheimer's disease (AD). Leptin is an anti-obesity hormone that modulates energy homeostasis and memory function. Although leptin deregulation is implicated in mouse models of AD-like brain pathology, clinical studies have shown inconsistent results regarding an association of leptin with the development of this neurodegenerative disorder.

We investigated the changes of plasma leptin and the correlation of sex-stratified circulating leptin with cognitive performance, AD-related biological markers, and metabolic status in patients with AD and cognitively unimpaired (CU) counterparts.

We used nonobese AD patients and CU controls in a University of Kansas Medical Center (KUMC) cohort. Plasma leptin levels, circulating AD-related molecules and metabolic profiles were examined and analyzed.

In contrast to unchanged circulating leptin in females, male patients exhibited decreased plasma leptin levels compared with male CU counterparts. Moreover, plasma leptin showed no correlation with cognitive performance and AD blood biomarkers in patients with either sex. Of note, females but not males demonstrated an association of plasma leptin with body mass index, high density lipoprotein-cholesterol and its ratio with total cholesterol and triglycerides.

Our findings suggest that leptin deficiency is associated with nonobese male AD patients, supporting systemic dysmetabolism in the development of this neurodegenerative disorder in certain populations. Although plasma leptin may have limited capacity to reflect disease severity or progression, future mechanistic studies on the regulation of leptin in nonobese patients with AD would deepen our understanding of the sex-related disparity of AD etiopathogenesis.

Alzheimer's disease (AD) is a complex age-related neurodegenerative disease, associated with central and peripheral metabolic anomalies, such as impaired glucose utilization and insulin resistance. These observations led to a considerable interest not only in lifestyle-related interventions, but also in repurposing insulin and other anti-diabetic drugs to prevent or treat dementia. Body temperature is the oldest known metabolic readout and mechanisms underlying its maintenance fail in the elderly, when the incidence of AD rises. This raises the possibility that an age-associated thermoregulatory deficit contributes to energy failure underlying AD pathogenesis. Brown adipose tissue (BAT) plays a central role in thermogenesis and maintenance of body temperature. In recent years, the modulation of BAT activity has been increasingly demonstrated to regulate energy expenditure, insulin sensitivity and glucose utilization, which could also provide benefits for AD. Here, we review the evidence linking thermoregulation, BAT and insulin-related metabolic defects with AD, and we propose mechanisms through which correcting thermoregulatory impairments could slow the progression and delay the onset of AD.

Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer's disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.