Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer's Disease.

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-ß (Aß) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor ß (TGFß) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFß increases during aging. Also, activin/TGFß signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aß42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFß receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

Noradrenaline as a key neurotransmitter in modulating microglial activation in stress response.

State of mind can influence susceptibility and progression of diseases and disorders not only in peripheral organs, but also in the central nervous system (CNS). However, the underlying mechanism how state of mind can affect susceptibility to various illnesses in the CNS is not fully understood. Among a number of candidates responsible for stress-induced neuroimmunomodulation, noradrenaline has recently been shown to play crucial roles in the major immune cells of the brain, microglia. In particular, recent studies have demonstrated that noradrenaline may be a key neurotransmitter in modulating microglial cells, thereby determining different cell conditions and responses ranging from resting to activation state depending on host stress level or whether the host is awake or asleep. For instance, microglia under resting conditions may have constructive roles in surveillance, such as debris clearance, synaptic monitoring, pruning, and remodeling. In contrast, once activated, microglia may become less efficient in surveillance activities, and instead implicated in detrimental roles such as cytokine or superoxide release. It is also likely that glial activation, both astrocytes and microglia, are negatively associated with the clearance of brain waste via the glymphatic system. In this review, we discuss the possible underlying mechanism as well as the roles of stress-induced microglial activation.

Connecting Alzheimer's Disease With Diabetes Mellitus Through Amyloidogenic Evolvability.

Type 2 diabetes mellitus (T2DM) has been clearlylinked to oxidative stress and amylin amyloidosis in pancreatic ß-cells. Yet despite extensive investigation, the biological significance of this is not fully understood. Recently, we proposed that Alzheimer's disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-ß (Aß) and tau, might be involved in evolvability against diverse stressors in the brain. Given the analogous cellular stress environments shared by both T2DM and AD, the objective of this study is to explore T2DM pathogenesis from the viewpoint of amyloidogenic evolvability. Similar to AD-related APs, protofibrillar amylin might confer resistance against the multiple stressors in ß-cells and be transmitted to offspring to deliver stress information, in the absence of which, type 1 DM (T1DM) in offspring might develop. On the contrary, T2DM may be manifested through an antagonistic pleiotropy mechanism during parental aging. Such evolvability-associated processes might be affected by parental diabetic conditions, including T1DM and T2DM. Furthermore, the T2DM-mediated increase in AD risk during aging might be attributed to an interaction of amylin with AD-related APs through evolvability, in which amylin protofibrillar formation presumably caused by adiponectin (APN) resistance could increase protofibril formation of AD-related APs in evolvability and subsequently lead to T2DM promotion of AD through antagonistic pleiotropy in aging. This suggests that targeting APN combined with an anti-T2DM agent might be therapeutic against neurodegeneration. Collectively, T1DM and T2DM might be linked through amylin evolvability, and a better understanding of amyloidogenic evolvability might also reveal clues to therapeutic interventions for AD comorbid with T2DM.

Adiponectin Paradox as a Therapeutic Target in Alzheimer's Disease.

Despite the apparent neurotoxicity of amyloid-ß (Aß), recent clinical trials of Aß immunotherapy have not shown any clinical benefit in Alzheimer's disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

Understanding Creutzfeldt-Jackob disease from a viewpoint of amyloidogenic evolvability.

Creutzfeldt-Jackob disease (CJD), the most common human prion disorder, is frequently accompanied by ageing-associated neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. Although cross-seeding of amyloidogenic proteins (APs), including amyloid ß and α-synuclein, may be critical in the co-morbidity of neurodegenerative disorders, the direct interaction of APs with prion protein (PrP), the central molecule involved in the pathogenesis of CJD, is unlikely. Currently, the nature of this biological interaction and its significance remain obscure. In this context, the objective of the present study is to discuss such interactions from the perspective of amyloidogenic evolvability, a putative function of APs. Hypothetically, both hereditary- and sporadic CJD might be attributed to the role of PrP in evolvability against multiple stressors, such as physical stresses relevant to concussions, which might be manifest through the antagonistic pleiotropy mechanism in ageing. Furthermore, accumulating evidence suggests that PrP- and other APs evolvability may negatively regulate each other. Provided that increased APs evolvability might be beneficial for acquired CJD in young adults, a dose-reduction of α-synuclein, a natural inhibitor of αS aggregation, might be therapeutically effective in upregulating APs evolvability. Collectively, a better understanding of amyloidogenic evolvability may lead to the development of novel therapies for CJD.

Adiponectin Paradox in Alzheimer's Disease; Relevance to Amyloidogenic Evolvability?

Adiponectin (APN) is a multi-functional adipokine which sensitizes the insulin signals, stimulates mitochondria biogenesis, and suppresses inflammation. By virtue of these beneficial properties, APN may protect against metabolic syndrome, including obesity and type II diabetes mellitus. Since these diseases are associated with hypoadiponectinemia, it is suggested that loss of function of APN might be involved. In contrast, despite beneficial properties for cardiovascular cells, APN is detrimental in circulatory diseases, including chronic heart failure (CHF) and chronic kidney disease (CKD). Notably, such an APN paradox might also be applicable to neurodegeneration. Although APN is neuroprotective in various experimental systems, APN was shown to be associated with the severity of amyloid accumulation and cognitive decline in a recent prospective cohort study in elderly. Furthermore, Alzheimer's disease (AD) was associated with hyperadiponectinemia in many studies. Moreover, APN was sequestered by phospho-tau into the neurofibrillary tangle in the postmortem AD brains. These results collectively indicate that APN might increase the risk of AD. In this context, the objective of the present study is to elucidate the mechanism of the APN paradox in AD. Hypothetically, APN might be involved in the stimulation of the amyloidogenic evolvability in reproductive stage, which may later manifest as AD by the antagonistic pleiotropy mechanism during aging. Given the accumulating evidence that AD and CHF are mechanistically overlapped, it is further proposed that the APN paradox of AD might be converged with those of other diseases, such as CHF and CKD.

Stress and brain immunity: Microglial homeostasis through hypothalamus-pituitary-adrenal gland axis and sympathetic nervous system.

Stress has been well documented to bring about various clinical disorders, ranging from neurodegeneration, such as Parkinson's (PD) and Alzheimer's diseases (AD), to metabolic disorders including diabetes mellitus. Importantly, microglia, immunocompetent cells in the brain, have been shown to be involved in these clinical disorders. In the recent studies aiming to clarify the microglial responses, microglia are found to be quite responsive to stressful events, such as acute, subchronic, chronic stress, and social defeat stress. However, the mechanisms of these stress response on microglial activation have been not fully understood. In response to stress exposure, both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are simultaneously activated, with the former inducing glucocorticoids (GCs) and the latter noradrenaline (NA), respectively. However, the effects of these stress-induced GCs and NA have not been consistent. The GCs, conventionally known to act on microglia as immunosuppressant, is also reported to act on it as stimulator. Similarly, the NA has been reported to act on microglia as stimulator or inhibitor depending on environmental conditions. Since any kinds of stress upregulate the HPA axis and SNS, with the levels of upregulation variable depending on the stress type, it is plausible that microglia is closely regulated by these two stress pathways. In this review, we discuss the microglial responses induced by various stresses as well as the possible mechanism by which stress induces microglial activation.

Stress-induced microglial activation occurs through ß-adrenergic receptor: noradrenaline as a key neurotransmitter in microglial activation.

BACKGROUND: The involvement of microglia in neuroinflammatory responses has been extensively demonstrated. Recent animal studies have shown that exposure to either acute or chronic stress induces robust microglial activation in the brain. In the present study, we investigated the underlying mechanism of brain microglial activation by acute stress. METHODS: We first looked at the spatial distribution of the noradrenaline (NA)-synthesizing enzyme, DBH (dopamine ß-hydroxylase), in comparison with NA receptors-ß1, ß2, and ß3 adrenergic receptors (ß1-AR, ß2-AR, and ß3-AR)-after which we examined the effects of the ß-blocker propranolol and α-blockers prazosin and yohimbine on stress-induced microglial activation. Finally, we compared stress-induced microglial activation between wild-type (WT) mice and double-knockout (DKO) mice lacking ß1-AR and ß2-AR. RESULTS: The results demonstrated that (1) microglial activation occurred in most studied brain regions, including the hippocampus (HC), thalamus (TM), and hypothalamus (HT); (2) within these three brain regions, the NA-synthesizing enzyme DBH was densely stained in the neuronal fibers; (3) ß1-AR and ß2-AR, but not ß3-AR, are detected in the whole brain, and ß1-AR and ß2-AR are co-localized with microglial cells, as observed by laser scanning microscopy; (4) ß-blocker treatment inhibited microglial activation in terms of morphology and count through the whole brain; α-blockers did not show such effect; (5) unlike WT mice, DKO mice exhibited substantial inhibition of stress-induced microglial activation in the brain. CONCLUSIONS: We demonstrate that neurons/microglia may interact with NA via ß1-AR and ß2-AR.

Possible Role of Amyloid Cross-Seeding in Evolvability and Neurodegenerative Disease.

Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding (CS) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological CS of multiple APs has also been observed in lower organisms, including yeast and bacteria. In this context, our main objective is to discuss a possible involvement of the CS of APs in promoting evolvability, a hypothetical view regarding the function of APs as an inheritance of acquired characteristics against human brain stressors, which are transgenerationally transmitted to offspring via germ cells. Mechanistically, the protofibrils formed by the CS of multiple APs might confer hormesis more potently than individual APs. By virtue of greater encoded stress information in parental brains being available, the brains of offspring can cope more efficiently with forth-coming stressors. On the other hand, subsequent neurodegeneration caused by APs in parental brain through the antagonistic pleiotropy mechanism in aging, may suggest that synergistically, multiple APs might be more detrimental compared to singular AP in neurodegeneration. Taken together, we suggest that the CS of multiple APs might be involved in both evolvability and neurodegenerative disease in human brain, which may be mechanistically and therapeutically important.

Current and future clinical utilities of Parkinson's disease and dementia biomarkers: can they help us conquer the disease?

Introduction: Biomarkers for Parkinson's disease and Alzheimer's disease are essential, not only for disease detection, but also provide insight into potential disease relationships leading to better detection and therapy. As metabolic disease is known to increase neurodegeneration risk, such mechanisms may reveal such novel targets for PD and AD. Moreover, metabolic disease, including insulin resistance, offer novel biomarker and therapeutic targets for neurodegeneration, including glucagon-like-peptide-1, dipeptidyl peptidase-4 and adiponectin. Areas covered: The authors reviewed PubMed-listed research articles, including ours, on a number of putative PD, AD and neurodegenerative disease targets of interest, focusing on the relevance of metabolic syndrome and insulin resistance mechanisms, especially type II diabetes, to PD and AD. We highlighted various issues surrounding the current state of knowledge and propose avenues for future development. Expert opinion: Biomarkers for PD and AD are indispensable for disease diagnosis, prognostication and tracking disease severity, especially for clinical therapy trials. Although no validated PD biomarkers exist, their potential utility has generated tremendous interest. Combining insulin-resistance biomarkers with other core biomarkers or using them to predict non-motor symptoms of PD may be clinically useful. Collectively, although still unclear, potential biomarkers and therapies can aid in shedding new light on novel aspects of both PD and AD.

Potentiating a non-neuronal cardiac cholinergic system reinforces the functional integrity of the blood brain barrier associated with systemic anti-inflammatory responses.

We previously reported that the heart-specific choline acetyltransferase (ChAT) gene overexpressing mice (ChAT tg) show specific phenotypes including ischemic tolerance and the CNS stress tolerance. In the current study, we focused on molecular mechanisms responsible for systemic and localized anti-inflammatory phenotypes of ChAT tg. ChAT tg were resistant to systemic inflammation induced by lipopolysaccharides due to an attenuated cytokine response. In addition, ChAT tg, originally equipped with less reactive Kupffer cells, were refractory to brain cold injury, with decreased blood brain barrier (BBB) permeability and reduced inflammation. This is because ChAT tg brain endothelial cells expressed more claudin-5, and their astrocytes were less reactive, causing decreased hypertrophy. Moreover, reconstruction of the BBB integrity in vitro confirmed the consolidation of ChAT tg. ChAT tg were also resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neuronal toxicity due to lower mortality rate and neuronal loss of substantia nigra. Additionally, ChAT tg subjected to MPTP showed attenuated BBB disruption, as evident from reduced sodium fluorescein levels in the brain parenchyma. The activated central cholinergic pathway of ChAT tg lead to anti-convulsive effects like vagus nerve stimulation. However, DSP-4, a noradrenergic neuron-selective neurotoxin against the CNS including the locus ceruleus, abrogated the beneficial phenotype and vagotomy attenuated expression of claudin-5, suggesting the link between the cholinergic pathway and BBB function. Altogether, these findings indicate that ChAT tg possess an anti-inflammatory response potential, associated with upregulated claudin-5, leading to the consolidation of BBB integrity. These characteristics protect ChAT tg against systemic and localized inflammatory pathological disorders, which targets the CNS.

Transgenerational Interaction of Alzheimer's Disease with Schizophrenia through Amyloid Evolvability.

Alzheimer's disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution.

Possible Role of the Polyglutamine Elongation in Evolution of Amyloid-Related Evolvability.

The polyglutamine (polyQ) diseases, such as Huntington's disease and the spinocerebellar ataxias, are characterized by the accumulation of elongated polyQ sequences (epolyQ) and mostly occur during midlife. Considering that polyQ disorders have not been selected out in evolution, there might be important physiological functions of epolyQ during development and/or reproduction. In a similar context, the physiological functions of neurodegeneration-associated amyloidogenic proteins (APs), such as ß-amyloid in Alzheimer's disease and α-synuclein in Parkinson's disease, remain elusive. In this regard, we recently proposed that evolvability for coping with diverse stressors in the brain, which is beneficial for offspring, might be relevant to the physiological functions of APs. Given analogous properties of APs and epolyQ in terms of neurotoxic amyloid-fibril formation, the objective of this paper is to determine whether evolvability could also be applied to the physiological functions of epolyQ. Indeed, APs and epolyQ are similar in many ways, including functional redundancy of non-amyloidogenic homologues, hormesis conferred by the heterogeneity of the stress-induced protein aggregates, the transgenerational prion-like transmission of the protein aggregates via germ cells, and the antagonistic pleiotropy relationship between evolvability and neurodegenerative disease. Given that epolyQ is widely expressed from microorganisms to human brain, whereas APs are only identified in vertebrates, evolvability of epolyQ is considered to be much more primitive compared to those of APs during evolution. Collectively, epolyQ may be not only be important in the pathophysiology of polyQ diseases, but also in the evolution of amyloid-related evolvability.

Evolvability and Neurodegenerative Disease: Antagonistic Pleiotropy Phenomena Derived from Amyloid Aggregates.

At present, the precise physiological role of neurodegenerative disease-related amyloidogenic proteins (APs), including α-synuclein in Parkinson's disease and ß-amyloid in Alzheimer's disease, remains unclear. Because of similar adaptability of both human brain neurons and yeast cells to diverse environmental stressors, we previously proposed that the concept of evolvability in yeast prion could also be applied to APs in human brain. However, the mechanistic relevance of evolvability to neurodegenerative disorders is elusive. Therefore, our objective is to discuss our hypothesis that evolvability and neurodegenerative disease may represent a form of antagonistic pleiotropy derived from the aggregates of APs. Importantly, such a perspective may provide an outlook of the entire course of sporadic neurodegenerative diseases.

Dual-therapy strategy for modification of adiponectin receptor signaling in aging-associated chronic diseases.

Given the paradigm of anti-insulin resistance in therapies for metabolic syndrome, there has been considerable interest in adiponectin (APN), an adipocyte-derived sensitizer of insulin receptor signaling. In contrast to hypoadiponectinemia in metabolic syndrome, evidence suggests that Alzheimer's disease (AD) and other diseases, including chronic heart failure (CHF) and chronic kidney disease (CKD), are characterized by hyperadiponectinemia as well as the APN/obesity paradoxes, indicating that a decrease in APN might also be beneficial for these diseases. Thus, distinct from metabolic syndrome, it is anticipated that APN receptor antagonists rather than agonists might be effective in therapy for some chronic diseases.

Evolvability of Amyloidogenic Proteins in Human Brain.

Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-ß and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin's 'gemmules', imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis.

Potential Application of Centrifuges to Protect the CNS in Space and on Earth.

OBJECTIVE: Centrifuges are the principal means of generating physiological hypergravity and have been used for many medical purposes, including the therapy of psychiatric diseases and evaluation of vestibular system in the pilots. In particular, modern centrifuges have evolved into mechanically sophisticated precision instruments compared to primitive ones in old times, indicating that centrifuges might possess great potential in modern medicine. Indeed, studies are in progress to apply centrifuges to musculoskeletal degenerative diseases, such as osteoporosis and sarcopenia. Given that the agingrelated diseases are manifested under microgravity conditions, including astronauts and the bed-ridden elderly, it is reasonable to speculate that centrifuge-induced hypergravity may counteract the progression of these diseases. Such a view may also be important for neurodegenerative diseases for which the radical treatments are yet to be established. Therefore, the main objective of this paper is to discuss a potential therapeutic use of centrifuges for protection against the central nervous system (CNS) disorders, both in space and on Earth. Mechanistically hypergravity may exert stimulatory effects on preconditioning, chaperone expression, synapse plasticity, and growth and differentiation in the nervous system. Furthermore, hypergravity may suppress the progress of type II diabetes mellitus (T2DM), leading to inhibition of T2DM-triggered CNS disorders, including neurodegenerative diseases, ischemia and depression. CONCLUSION: Moreover, it is possible that hypergravity may counteract the neurodegeneration in hippocampus induced by the microgravity conditions and psychiatric diseases. Collectively, further investigations are warranted to demonstrate that centrifuge-induced hypergravity may be beneficial for the therapy of the CNS disorders.

Motor and Nonmotor Symptoms of Parkinson's Disease: Antagonistic Pleiotropy Phenomena Derived from α-Synuclein Evolvability?

Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-ß (Aß) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease.

A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both 'gain of function' and 'loss of function' of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

Combined immunotherapy with "anti-insulin resistance" therapy as a novel therapeutic strategy against neurodegenerative diseases.

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid ß and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid ß immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid ß monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "anti-insulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy.