Abstract

1. Introduction

When focusing on dementia, it is worth noting that the separating line between normal and pathological aging is not adequately defined. Therefore, it is difficult to determine where each phenomenon begins and ends and to distinguish the common deficiencies and individual differences within these phenomena [1]. This narrow line that separates the normal from the pathological is where we must intervene to minimise the symptoms the disease produces, making an early diagnosis of dementia necessary. The difficulty is even greater taking into account that the aging process itself can produce negative effects on general health and cognitive function in particular. Similarly, aging is linked to an increase in body weight, adiposity, and variations in hormones and adipokines, showing an altered pattern with age [2,3]. Similarly, both in murine and human models, an increase in microglial reactivity and inflammation with age has been described [2,3]. In this review, we discuss how this altered pattern is a factor that predisposes to obesity and dementia, such as Alzheimer’s disease (AD).

Procedures have been developed over time to identify patients with early onset dementia, a concept that has evolved into the current term, mild cognitive impairment (MCI). Ronald Petersen developed the concept of MCI through the Mayo Clinic. The concept was an improvement in its attempt to identify people who may progress to dementia, as the cognitive aspects were introduced to the pre-existing aspects of memory. Currently, the fundamental objective of dementia research is to find markers that provide an early diagnosis and thus enable action to be taken before the disease evolves [1]. MCI is an example of this.

Today, obesity is growing in the global population due to multiple causes: lifestyle, stress, nutrition, genetic background, and lack of exercise. In obesity, white adipose tissue (WAT) not only stores excess energy but also disturbs endocrine function. WAT secretes a group of substances called adipokines that exert autocrine, paracrine, and endocrine effects at the systemic level and also centrally in the central nervous system (CNS) [4,5,6]. Obesity has been linked to cognitive deficits, impaired long-term potentiation and synaptic plasticity, and a smaller brain volume, increasing the probability of developing Alzheimer’s disease (AD) and other dementias [7]. Thus, obesity is established as a risk factor for dementia. Furthermore, obesity causes a state of low-grade chronic inflammation in adipose tissue that leads to the dysregulation of homeostatic systems, which in turn leads to the development of various diseases, including those related to neurodegeneration. During this process, adipose tissue produces an increase in pro-inflammatory adipokine levels (interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumoural necrosis factor alfa (TNF-α), and leptin) and a decrease in anti-inflammatory adipokine levels, such as adiponectin [4,6]. Yet another essential component of these complex interrelationships between obesity and brain status is the gut microbiota. In fact, meticulously detailed in a review by authors [8], it is explained how an altered intestinal microbiota pattern (or dysbiosis) can lead to a permanently altered physiological pattern, which can lead to cognitive impairments due to alterations in the gut-brain axis. In addition, it indicated that the administration of pre- and probiotics can restore this dysbiosis, enabling a return to an adequate homeostatic balance.

Leptin, a pro-inflammatory adipokine secreted by WAT and found to be increased in people with a high body mass index, acts centrally at the level of the hypothalamic region through anorexigenic proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, controlling food intake and energy expenditure. The literature suggests that leptin may be the link between obesity and dementia through the development of inflammation. Therefore, we will analyse the information on inflammation-induced leptin resistance that occurs during obesity as a pathological mechanism that may underlie neurodegenerative diseases such as AD and other dementias.

2. Obesity and Dementia

Obese individuals are at greater risk of developing age-related cognitive decline, vascular dementia, MCI, and AD [4], as well as other neurodegenerative pathologies such as Parkinson’s [9,10] and Huntington’s disease [10,11]. In this section, we give an overview of obesity as a risk factor for dementia based on adipose tissue measurement indices, brain structural changes, and cognitive impairment measurements. Our purpose is to identify modifiable risk factors that allow an early diagnosis and treatment.

Obesity can be defined as an excessive accumulation of adipose tissue which generates a low-grade inflammation state, whereas AD can be defined as a progressive neurodegenerative disease whose distinctive histopathological characteristics are the extracellular amyloid plaques and intracellular neurofibrillary tangles.

A parameter used as a measure of adiposity is the body mass index (BMI). However, its use has not been free from difficulties. That is why the waist circumference and the waist-to-hip ratio (WHR) have also been used to evaluate excess fat [12]. In fact, in the work by Beyer et al. (2019) [12], it is suggested that the WHR, as part of a metabolic obesity profile, is a determining factor that plays a role in grey matter volume reductions, which might lead to reduced cognitive functions, that have a weaker association when using the BMI [12,13]. Nevertheless, BMI is the most widely used adiposity index [14,15,16]. Thus, an association between BMI and dementia has been described, although this relation is controversial [14,15,16,17]. Firstly, it has been suggested that being overweight and obese in middle age is related to a higher risk of dementia in old age. Nevertheless, a high BMI in late life is associated with better cognition [6,16,17]. Secondly, other studies have described contradictory outcomes, where a lower risk of dementia was observed for very obese people (BMI > 40 kg/m2) while underweight people (BMI < 20 kg/m2) display a higher dementia risk than heavyweight people [18]. There are different epidemiological studies that relate obesity and dementias, such as the more frequent AD, but, in general, these studies find a positive correlation between obesity and cognitive impairment, with a possible U-shaped curve. In this context, a reverse relation has been described between obesity and grey matter and whole brain volume [19,20,21,22,23,24,25], even though a minor number of publications did not find such a relation [26,27].

As mentioned above, obesity generates a chronic low-grade inflammation state, which is characteristic of a variety of other chronic conditions, such as metabolic syndrome, non-alcoholic fatty liver disease, type 2 diabetes mellitus, and cardiovascular disease [28,29], as well as neuroinflammation [30,31,32], a hallmark of neurodegenerative diseases such as AD [33,34,35]. Following this line, different animal studies have confirmed the connection between obesity and cognitive mismatches and/or impairment. Thus, different works point to an altered cognitive function when administering a less-healthy diet. A high-fat diet (HFD) rich in saturated fatty acids can result in obesity as well as deficits in hippocampal-dependent learning and memory functions [36,37]. Male Wistar rats fed with a HFD showed impaired memory, an effect that was augmented with a longer duration of HFD consumption [38] while, similarly, rats fed with a high-fructose-high-coconut oil diet experienced impaired hippocampal-dependent learning and memory processes, as evaluated through the Morris water maze task [39]. In another study [40], HFD-induced brain insulin resistance and cognitive impairment were observed. Molecular changes, such as a significant decrease in tyrosine phosphorylation of the insulin receptor and increased serine phosphorylation of IRS-1, which are signs of insulin resistance, might be the cause of the cognitive impairment in this mouse model. These molecular changes were accompanied by inflammatory signalling (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In a transgenic rat model of pre-AD and MCI, impaired special learning and memory has been described in the Morris water maze when rats received a high-caloric diet [41]; at the same time, some parameters of brain inflammation, such as microgliosis, were also found. Moreover, activated OX-6+ microglia were detected, as well as GFAP+ astrocytes located predominantly in the white matter, and the synaptic density in the CA1 and CA3 hippocampal subregions was lower in this high-calorific diet. In a triple transgenic AD mice model (3xTg-AD), an impairment in the cognitive function has been shown when administering a HFD, and this diet was able to induce enhanced oxidative stress and aggravated neuronal apoptosis via inactivation of the Nrf2 signalling pathway [42]. So, numerous animal studies indicate the relation between obesity and AD and other forms of dementia that affect cognitive function.

Overall, obesity seems to be a risk factor for different forms of dementia, where we can find long-term memory and attention impairment, and executive function deficits. We have reviewed how cerebral structural and functional changes in obese people occur, and how a high saturated fat diet can affect cognitive function, including brain inflammation as a hallmark of this process.

3. Obesity and Leptin

Energy homeostasis and the maintenance of body weight require that the peptides secreted by the organs of the periphery establish a signalling and functional interrelation between them. To do this, adipocytes synthesise and secrete adipokines with pleiotropic effects in various tissues and regulate numerous physiological functions [43,44]. In this review, we will focus on leptin, due to its involvement in the regulation of food intake and energy expenditure, studying its involvement in dementia and its relationship with obesity.

Leptin has been found to circulate in plasma in proportion to body fat mass and this can be taken as an indicator of adiposity [45,46]. However, its study is difficult, since its levels vary by multiple factors: sex, BMI, starvation, and energy states. In addition, it shows a circadian rhythm, with leptin levels at their maximum between midnight and dawn, and is affected by other hormones and cytokines [47]. Leptin is a 16 kilodalton (kDa) peptide hormone produced by the ob (obese) gene. Leptin receptors are class I cytokine receptors. Previous studies have described six isoforms of the mRNA variants of the gene encoding the leptin receptor: four short forms (LepRa, LepRc, LepRd, LepRf), one long form (LepRb), and an extracellularly secreted soluble form (LepRe) [48]. Furthermore, five of the six isoforms (LepRa-LepRd and LepRf) have common extracellular and transmembrane domains, and only the soluble form (LepRe) has only an extracellular domain [48]. The long form LepRb has intracellular domains and proline-rich regions known as box1, box2, and box3 that are associated with Janus kinase (JAK) and signal transducer activators of transcription (STAT) signalling activation, whereas the other isoforms seem to be implicated in the leptin transport from the periphery to the CNS through the blood-brain-barrier (BBB) [48,49,50,51,52]. Leptin receptors are expressed throughout the body. In the CNS, leptin receptors are expressed in the arcuate nucleus (ARC), the dorsomedial hypothalamus (DMH), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH), the mediobasal hypothalamus (MBH), and the paraventricular nucleus (PVN). In addition, they have also been found in the cerebral cortex, hippocampus, ventral tegmental area, substantia nigra, medulla, and cerebellum [48,50,52,53,54,55,56,57]. Furthermore, the short isoforms LepRa and LepRc are expressed in the brain microvessels that make up the BBB, suggesting that these receptors may be associated with leptin transport [53,54]; in fact, the LepRa and LepRc isoforms have been shown to mediate leptin transport in the BBB, and dysfunctional receptors can lead to leptin resistance [56]. The expression of the leptin receptor has been observed in different neurons, including glutamatergic, GABAergic, and dopaminergic neurons. Thus, there is evidence of its involvement in the mechanisms of long-term potentiation, long-term depression, and motivational eating [42,44,45,48,49].

Biochemically, when leptin binds to its receptor it allows the activation of Janus kinase 2 (JAK2) and its autophosphorylation. Once activated, JAK2 phosphorylates other tyrosine residues (Tyr) in the receptor, including Tyr985, Tyr1077, and Tyr1138, to mediate different intracellular signalling pathways [48,58,59]. Intracellular signalling pathways initiated by the leptin receptor are [48,53,58,60,61]:

1. JAK/signal transducer activators of transcription 3 (STAT3);

2. Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt);

3. Extracellular signalling-regulated kinases (ERK); and

4. Signal transducer activators of transcription 5 (STAT5).

As we will see below, leptin is involved in various aspects of cognition, neurogenesis, neuroprotection, synaptic plasticity, and structural changes [57,62], which is not surprising given its access from the periphery to the CNS, the number of leptin receptors, and its wide distribution in the brain.

4. Leptin; Its Relationship with Cognition and Synaptic Function

An important aspect of dementia is cognitive deterioration, which is manifested in different aspects such as synaptic function, learning, and memory. So, before addressing the connection between leptin and dementia, it is important to analyse the relationship and implication of leptin with these different aspects of cognition. Leptin signalling regulates different processes including food intake, energy expenditure, cognition, learning, memory, and mood [63]. Studies show that leptin performs different neuroprotective functions [56,57,63,64,65]. Furthermore, leptin regulates neurogenesis, synaptogenesis, neuronal excitability, and neuroprotection [57,62].

In learning and memory processes, synaptic plasticity, and the relationships between neurons at the level of synaptic transmission, are fundamental. Furthermore, in these processes, the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are crucial for the formation and consolidation of hippocampal memory. Thus, leptin is involved in these processes at the level of the hippocampus where leptin and glutamate receptors {N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors} are key players [4,50,59]. In support of this evidence, leptin receptors have been found in neuronal and non-neuronal cells in the hypothalamus, the cerebral cortex, as well as in the dentate gyrus, and the CA1 and CA3 areas of the hippocampus [62]. This last finding is fundamental, as these areas are highly involved with cognition and memory. Recent studies indicate that NMDA receptors are necessarily involved in leptin-dependent homeostatic control of body weight [66]. Thus, leptin enhances NMDA receptor function by promoting the efficiency of excitatory synaptic transmission at hippocampal Schaffer-collateral (SC)-CA1 synapses and allowing the conversion of short-term potentiation into LTP. Therefore, it is not surprising to have found LTP and LTD deficiencies in leptin-insensitive obese mice (db/db) and rats deficient in the leptin receptor (fa/fa) [4,59]. Consequently, leptin improves hippocampal-dependent memory. Thus, in the review by McGregor and Harvey [66] it is found that in transgenic mouse models of Alzheimer’s disease (CRND8), leptin improved performance in object recognition, contextual, and fear-conditioned tasks. In addition, performance in hippocampal-dependent memory tasks was also optimised in mice prone to accelerated senescence (SAMP8) that have elevated levels of the β-amyloid peptide (Aβ).

Leptin can also regulate the configuration of neurons. Thus, plasma leptin levels have been associated with grey matter volume in various brain regions. Exogenous leptin administration recovers structural brain abnormalities in congenitally leptin-deficient humans and reverses the abnormalities in ob/ob mice [62]. Interestingly, the study by Annweiler [64] finds a relationship between circulating leptin levels and U-shaped cognition. Their results suggest that older adults with low or high circulating leptin concentrations are particularly prone to cognitive impairment and point to leptin as a modifiable risk factor.

Therefore, we can say that leptin, through its actions in the periphery or the CNS, produces neuroprotective effects that improve cognitive function and memory. As a result, its dysfunction due to a deficit in signalling pathways, a decrease or alteration of its levels, or leptin resistance can cause processes that promote neurodegeneration [62].

5. Leptin Resistance: Mechanisms Involved

Leptin is reduced during fasting and increases with food consumption. When we eat, adipocytes release leptin, which tends to reduce eating behaviour. However, the paradox exists that in obesity, the leptin levels are increased; despite this, there is no indication or signal of satiety due to a peripheral and/or central resistance to leptin. Thus, an imbalance between anorexigenic and orexigenic signals occurs, which leads us to receive a signal of decreased satiety, and contributes to obesity, leading to a vicious cycle [4,61].

Resistance to leptin indicates that despite high plasma levels in obese people, signalling in the hypothalamus is decreased [4]. The foregoing leads us to review and analyse the factors involved in this dysfunction in leptin signalling. Next, we analyse the mechanisms that have been proposed as an explanation for leptin resistance, which is related to obesity, and helps to develop or perpetuate diseases such as dementia: (a) genetic mutations, (b) alterations in the transport of leptin through the BBB, (c) desensitisation of leptin receptors that reduce the functionally active number, (d) attenuation of signalling leptin {suppressor of cytokine signalling type 3 (SOCS3), protein tyrosine phosphatase type 1B (PTP-1B), and protein tyrosine phosphatase of T cells (TCPTP)}, (e) alteration of cellular descending leptin signalling in the CNS, and (f) multiple factors such as inflammation, elevated levels of C-reactive protein (CRP), adapter protein1 (SH2B1), and endoplasmic reticulum (ER) stress as well as decreased activity of histone deacetylase and the type of diet [58,61,67,68,69,70]. In this context, obesity-related inflammation may contribute to leptin resistance, which in turn further increases weight gain [71] and leptin levels, which then increases the inflammation-related obesity, since leptin is an important proinflammatory adipokine [72,73,74], activating monocytes [75] and lymphocytes [76].

6. Leptin Signalling, Obesity, and Alzheimer’s Disease

There is a rare and genetically established form of Alzheimer’s disease (AD) and a sporadic form which is the most common in Alzheimer’s patients. In turn, there are genetic variants associated with an increased risk for Alzheimer’s disease. The best known is a variant of the gene encoding apolipoprotein E (APOE), the variant being APOE4 [120]. Furthermore, the disease is associated with the formation of extracellular β-amyloid (Aβ) plaques and the accumulation of hyperphosphorylated tau proteins in the brain. Mitochondrial dysfunction is a key process underlying AD pathology, where mitophagy (or selective degradation of mitochondria by autophagy) and autophagic pathways seem to be altered in this pathology [121]. Indeed, these processes, when inadequately regulated, contribute to synaptic dysfunctions and cognitive impairments through the accumulation of Aβ fibrils and hyperphosphorylated tau protein tangles. Moreover, the transcription factor EB (TFEB) has been described as a molecular target to treat neurodegenerative disorders such as AD, Parkinson’s disease, or Huntington’s disease. TFEB is a principal regulator of autophagy and lysosomal biogenesis pathways [122], the malfunction of which leads to neuronal death. Moreover, phytoconstituents have been proposed as potential therapeutic remedies to manage AD [123]. The same work indicates the use of nanocarrier systems, whose use led to the correct delivery of herbal medicaments to a specific target, although the use of phytoconstituents is limited due to their low solubility and metabolism. Additionally, compounds have been developed with therapeutic applications for the symptomatic effects of AD, such as oxidative stress and learning and memory [124,125]. These are the piperazine derivative biphenyl-3-oxo-1,2,4-triazine and benzoxazole derivatives which seem to act as cholinesterase inhibitors and have antioxidant properties, enhancing learning and memory. Similarly, in AD, there is not only synaptic dysfunction but also neuroinflammation and oxidative damage that affects episodic memory and leads to impaired cognitive functions which cause interference in patients’ lives [126,127]. Obesity is also a risk factor for dementia and Alzheimer’s disease.

Given the relationship between obesity and dementia, some scientists are beginning to investigate a link with leptin. AD has been considered as a brain-type metabolic disorder [126,128,129] which requires a readjustment of homeostasisq and is influenced by inflammation, adipokines, adipocyte-derived hormones, and the various exposed mechanisms of leptin resistance. Thus, neuronal resistance to leptin is suggested in AD [130,131].

The link between obesity, leptin, and AD is now well established and has been extensively studied. Thus, different epidemiological studies have found an association between AD and changes in body weight. Some reports have found that obesity in midlife, as well as weight loss in old age, are related to cognitive decline and increased risk of developing AD [62,132,133,134]. Diets rich in saturated fatty acids have also been associated with an increased risk of AD in several animal and human studies [133] and several studies have found an association between a low body mass index (BMI) and AD in post-mortem brains [62,133]. Furthermore, it has also been suggested that WHR, but not BMI, was correlated with an increased risk of AD [132]. However, a study from the United Kingdom shows that the chance of developing AD is lower in obese middle-aged people but higher in middle-aged and older people of low weight [62,133]. In summary, although there is no unanimity across the studies, most of the evidence suggests that the increase in adiposity during middle age influences the risk of developing dementia, as well as its reduction in old age. So, as the disease develops before the appearance of cognitive symptoms, it is suggested that low weight in old age may be a manifestation of this early stage of the disease and a sign of premature brain dysfunction [62,133]. In support of this notion, low BMI has been found to be associated with the deterioration of AD pathology in postmortem brains, as well as the worsening of CSF biomarkers {tau and amyloid-β peptide form (Aβ1-42)} [62,133]. Interestingly, some models have been proposed to explain weight change at different stages of AD [62,133].

It has been shown that leptin is secreted by adipocytes and circulates in plasma in proportion to fat mass [48,63,130], and changes in body weight are associated with the possibility of developing AD. Therefore, it is not surprising that different investigations try to relate dysfunctional levels in leptin signalling with AD. Thus, in some studies, low plasma leptin levels in old age have been found to be associated with an increased risk of cognitive decline and AD development [62,134]. Similarly, the authors of one study show that plasma leptin levels are lower in subjects with mild cognitive impairment (MCI) or AD compared to control subjects and confirm a decrease in Aß42 and an increase in the tau protein related to MCI and AD. In addition, the same study suggests that plasma leptin deficiency could indicate a possible CNS leptin deficiency and thus serve as a diagnostic marker for MCI or AD [135]. Several studies also reported the same evidence in subjects with MCI or AD [4,62,136].

Not all studies have found an association between circulating leptin levels and AD or cognitive decline; one study finds no relationship between leptin levels and cognition, or disease severity in AD patients. Moreover, unlike other previous investigations that found positive correlations between leptin levels, BMI, body weight, and mean waist circumference, they also found no correlation between leptin levels and the aforementioned measures [137]. Similarly, another recent report finds that serum leptin levels were similar in young patients (mean 60 years) diagnosed with AD and vascular dementia, compared to healthy controls and patients with subjective memory complaints, and concluded that peripheral leptin levels do not play a role in the evolution of AD pathology [138]. Similarly, another current study reported no significant change in CSF leptin levels in AD compared to controls, at least in the early phases of AD progression during which the BBB remains intact [130]. These contradictory aspects have been explained by methodological differences or deficiencies and the complexity of leptin itself, although a non-linear U-shaped relationship has also been proposed, as we mentioned previously [64].

On the other hand, evidence suggests that leptin is involved in memory impairments that occur in hippocampal-dependent AD. Thus, leptin treatment improves performance on hippocampal-dependent memory tasks in SAMP8 mice that have elevated Aβ levels [66] and prevents the detrimental effects of Aβ on LTP and LTD in the hippocampus, as well as on AMPA receptor trafficking, and inhibits Aβ-induced up-regulation of endophilin 1 expression. In addition, there is evidence indicating that toxic Aβ levels decrease with leptin treatment. Thus, the authors suggest a dysfunction of the leptin signalling cascade involved in Aβ actions at hippocampal synapses [59,66]. In view of this evidence, a relationship between leptin and AD can be assumed in which very high levels of leptin, probably due to leptin resistance, as well as low leptin levels are associated with a higher risk of AD.

It seems that the leptin detected in the brain comes from the periphery [130]. Therefore, analysing the transport of leptin through the BBB and its integrity is essential to understanding the levels of leptin and its signalling in the brain. Although the BBB has been shown to be compromised in AD brains, it appears that such impairment may occur late in the disease [130]. Thus, a study that analysed whether leptin levels change as the subject progresses towards AD found no differences in these leptin levels in the CSF in the early stages of AD progression, nor did it detect changes in the CSF albumin/serum albumin ratio, reflecting the integrity of the BBB. For the authors of the study, these results suggest that leptin levels are intact, but leptin signalling is altered in AD [130]. We can conclude that the integrity of the BBB may be affected in the advanced phase of the disease and there seems to be a serious disconnection in the leptin signalling pathway in AD. In fact, a central resistance to leptin is mentioned in AD by detecting reductions in some signalling pathways that are activated downstream of leptin receptors [130].

It has been detected that the expression of the leptin receptor is altered in AD. Thus, in one study, it was found that the expression level of LepRb mRNA was lower in hippocampal tissue with AD compared to controls. Similarly, this study suggests a possible blockade induced by neurofibrillary tangles (NFT) to the accessibility of LepRb; thus, the leptin receptor is sequestered in regions with high concentrations of NFT which causes it to lose its signalling capacity. The lack of signalling results in the interpretation that there are inadequate circulating leptin levels, leading to increased leptin secretion and leptin resistance in these affected neurons [131]. Similarly, in another study with young and old mutant mice expressing APPSWE (Tg2576), a reduction in leptin was detected in neurons compared to those of control animals and young Tg2576 mice have also been found to have enhanced expression of LepRb, which is not seen in old Tg2576 mice. Therefore, a dysfunction in leptin signalling is suggested [130].

We might say that age is an important risk factor for dementia and specifically for AD. Similarly, diet, lifestyle, and stress also influence the development of dementia and low weight in old age and obesity in middle age are predisposing factors. Furthermore, the data analysed suggest that obesity in midlife and the elevated leptin levels seen in the obese lead to leptin resistance in the brain, which also predisposes to AD. Subsequently, before the manifestations of the disease, obesity-induced systemic inflammation will lead to neurodegeneration, which increases with age, where leptin signalling pathways are affected, altering their function.

Therefore, inflammation is involved in neurodegeneration, and it is present in the pathophysiology of AD. The peptide β-amyloid (Aβ) has been observed to influence the function of adipose tissue. Thus, it has been found that the fragment of the β-amyloid peptide (Aβ25-35) through protein kinase A (PKA) and ERK 1/2 dependent signalling pathways, can cause an increased release of free fatty acids and proinflammatory adipokines that can produce lipotoxicity in other organs [139]. Likewise, a high sucrose diet (HSD) fed to male APPswe/PS1dE9 (APP/PS1) transgenic mice induced an increase in neuroinflammation, as well as an increase in cortical and serum levels of β-amyloid. This work demonstrates that a HSD increases AD-related pathologies and reduces hypothalamic leptin signalling in APP/PS1 mice [140]. Similarly, a study investigating amyloid β-secretase (BACE1)-dependent processing in relation to leptin resistance demonstrates the need for functional leptin signalling and shows that reducing BACE1 activity is found to restore leptin sensitivity, normalise hypothalamic inflammation, and reduce PTP1B and SOCS3 [141].

However, it seems that Aβ and tau cannot fully explain the pathology of AD. Thus, a study has found a decrease in STAT5B and SOCS(1-3) in the brains of transgenic mice (APP/PS1) at 3 months of age. These results demonstrate a significant impairment in adipokine receptor signalling pathways in the hippocampus of APP/PS1 mice at a young age, before Aβ plaque formation [128]. Similarly, in another study using high-fat diet (HFD)-treated (APP/PS1) transgenic mice, leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice, suggesting impaired signalling of leptin in the hypothalamus, but hyperphagia and aggravated obesity were caused before the presence of amyloid pathology [142].

As mentioned in the previous section, protein tyrosine phosphatase 1B (PTP1B) is another mechanism involved in leptin resistance and works by modulating signalling pathways related to learning and memory, endoplasmic reticulum (ER) stress, and microglia-mediated neuroinflammation [143]. Therefore, the effects of its inhibition merit further investigation.

On the other hand, leptin, through its signalling pathways, can modify beta-amyloid peptide (Aβ) levels by blocking β-secretase activity and increasing ApoE-dependent amyloid beta uptake; it can also enhance Aβ peptide clearance by promoting its clearance and degradation [137]. Furthermore, leptin inactivates glycogen synthase kinase 3 β (GSK3β), the protein primarily responsible for tau hyperphosphorylation [127,132]. Adenosine monophosphate protein kinase (AMPK)/sirtuin1(SIRT1)-activated pathways appear to mediate the reduction of β-secretase activity by leptin, and AMPK, Akt protein, and p38 protein pathways mediate the reduction of tau phosphorylation by leptin [62].

So, LepRb, expressed in the hippocampus, triggers leptin signalling via Janus Kinase 2 (JAK2), which, in turn, phosphorylates three tyrosine residues in the LepRb intracellular domain (Tyr985, Tyr1077, and Tyr1138). Tyr1138 mediates the activation of STAT3 [144]. STAT3 is a transcription factor that, phosphorylated by JAK2, dimerises, and is translocated to the nucleus, where it controls the transcription of specific genes, within which is the suppressor of cytokine signalling 3 (SOCS3), a negative regulator of LepRb intracellular signalling [145,146]. The phosphorylation in Tyr1077 induces STAT5 activation [147]. Phosphorylated Tyr985 recruits the SH2-containing tyrosine phosphatase-2 (SHP-2) to mediate the activation of the MAPK pathway (extracellular signal-regulated kinase or ERK) [144,148]. Activated JAK2 can initiate the PI3K/Akt signalling pathway through the phosphorylation of IRS protein [144] which leads to the mammalian target of rapamycin (mTOR) activation, which influences the synthesis and aggregation of Tau, compromising microtubule stability when mTOR is inactivated [149]. Moreover, the PI3K/Akt signalling pathway can also inactivate glycogen synthase kinase 3 β (GSK3β), which, in turn, is unable to phosphorylate the Tau protein [150,151], thereby unfavouring the Tau aggregation characteristic of AD. Another key downstream effector of LepRb includes AMP-activated protein kinase (AMPK), which is phosphorylated by JAK2 [152]. AMPK may, in turn, induce a decrease in tau phosphorylation and β-amyloid accumulation [153]. These effects are PGC-1α-mediated, which is a coactivator of peroxisome proliferator-activating receptor γ (PPARγ), a transcriptional activator of target genes, regulating the transcription of BACE1, which is reciprocally regulated with respect to PGC-1α expression [154]. BACE1 is a key enzyme involved in Aβ generation, the hallmark harmful peptide of AD. A reduction in the activity and expression levels of BACE1, with a decreased production of Aβ after leptin stimulation, has been described [155]. Conversely, leptin signalling can be reduced by contra-regulatory mediators, such as SOCS3 and protein tyrosine phosphatase 1B (PTP1B). After leptin binding to its LepRb receptor, SOCS3 interferes with LepRb/JAK2 signalling [145], whereas PTP1B has the ability to dephosphorylate JAK2 [156]. Research has shown that mRNA, SOCS3, and PTP1B, are up-regulated in the hippocampus of an animal model of AD [157], suggesting that they may generate leptin resistance. (Figure 1).

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Figure 1

Leptin signalling in a hippocampal neuron. Leptin, mainly released by adipose tissue, reaches a hippocampal neuron where, binding to LepRb, activates the JAK/STAT, PI3K/Akt, and AMPK signalling pathways. PI3K/Akt pathway activation leads to mTOR activation, influencing synthesis and aggregation of Tau, as well as GSK-3β inactivation, which, in turn, is not able to hyperphosphorylate Tau. AMPK pathway activation leads to PGC-1α and PPAR activation, which, translocated to the nucleus, inhibit BACE1 transcription and decrease Aβ production. SOCS3 and PTP1B are negative regulators of leptin signalling acting on JAK2 and, therefore, generate leptin resistance that may cause the worsening of AD.

In summary, it can be said that LepRb signalling pathways seem to be clearly involved in AD. We can postulate that obesity in midlife increases the risk of AD by promoting systemic inflammation and leptin resistance, which leads to brain neurodegeneration. Subsequently, neurodegeneration worsens, creating a vicious cycle that leads to AD pathology where inflammation and oxidative stress become important factors in its development and progression [126].

7. Conclusions

Because obesity is a risk factor for AD and other dementias [4,6,50,52], effective markers should be determined in order to prevent adverse effects, as well as begin comprehensive programs for prevention. Indeed, AD and obesity share common metabolic characteristics. Thus, adipokines, secreted by adipose tissue, communicate with the CNS, playing a role in the progression of AD and other dementias [6]; among them, leptin [4] has neuroprotective effects at the level of CNS [63,65]. Properly identifying the alterations in the signalling pathways triggered by leptin and its receptor, LepRb, is necessary in AD in order to reverse the dysfunction of these pathways and consequently improve the prognosis of AD. In fact, different mechanisms of leptin resistance have been described, among which are those carried out by SOCS3, PTP1B, and TCPTP, where SOCS3 and PTP1B have an altered expression level in an animal model of AD [157], disrupting leptin signalling. Thus, research should be aimed at the design of inhibitors or related mechanisms to reduce this resistance to leptin. In fact, the design of inhibitors against protein tyrosine phosphatases is possible [104], and the use of ATR inhibitors to reduce SOCS3 expression has also been suggested [103]. CNS inflammation or neuroinflammation is an important factor in the development and progression of neurodegenerative diseases [29,30,31], such as AD, PD, or HD, and inflammation can affect leptin-triggered signalling, leading to leptin resistance [158]. Thus, the use of anti-inflammatory drugs combined with those that reduce leptin resistance could be useful.

Funding Statement

PAIDI CTS-151 Junta de Andalucia, Spain.

Author Contributions

J.A.F.-C. and A.F.-B. wrote the draft, A.P.-P. and G.A. revised the references and text. C.J.-C. made the picture and revised the manuscript, V.S.-M. carried out conceptualization, coordination and revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

References