[Widely Applicable Strategies Against Cancer, Type II Diabetes, and Neurodegenerative Diseases by Means of Rationally Designed Anti-Amyloidogenic Molecules].

An increasing number of amyloidogenic proteins are being recognized for their contribution to the progression of various diseases, including cancer, type II diabetes, and neurodegenerative diseases. Detailed analyses of amyloids using cryo-electron microscopy have led to the development of rationally designed inhibitors of amyloid protein aggregation. In this review, we focused on widely applicable strategies against multiple amyloidogenic proteins based on the use of engineered molecules, namely peptidomimetic foldamers, steric zipper inhibitory peptides, di-phenyl-pyrazole derivatives, and chemicals involved in the disaggregation of amyloid fibrils. These strategies could facilitate efficient drug design across disease categories.

Therapeutic Potential of α-Synuclein Evolvability for Autosomal Recessive Parkinson's Disease.

The majority of Parkinson's disease (PD) is sporadic in elderly and is characterized by α-synuclein (αS) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage. Since no radical therapies are available for PD, the objective of this paper is to discuss a mechanistic role for amyloidogenic evolvability, a putative physiological function of αS, among PD subtypes, and the potential relevance to therapy. Presumably, αS evolvability might benefit familial PD due to autosomal dominant genes and also sporadic PD during reproduction, which may manifest as neurodegenerative diseases through antagonistic pleiotropy mechanism in aging. Indeed, there are some reports describing that αS prevents apoptosis and mitochondrial alteration under the oxidative stress conditions, notwithstanding myriads of papers on the neuropathology of αS. Importantly, ß-synuclein (ßS), the nonamyloidogenic homologue of αS, might buffer against evolvability of αS protofibrils associated with neurotoxicity. Finally, it is intriguing to predict that increased αS evolvability through suppression of ßS expression might protect against autosomal recessive PD. Collectively, further studies are warranted to better understand αS evolvability in PD pathogenesis, leading to rational therapy development.

Diabetes, inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2.

Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and 'cytokine storm,' causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.

Therapeutic Potential of αS Evolvability for Neuropathic Gaucher Disease.

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson's disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of ß-synuclein (ßS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer's disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid ß and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.

Adiponectin paradox as a therapeutic target of the cancer evolvability in aging.

Recent study suggests that protofibril-formation of amyloidogenic proteins (APs) might be involved in evolvability, an epigenetic inheritance of multiple stresses, in various biological systems. In cancer, evolvability of multiple APs, such as p53, γ-synuclein and the members of the calcitonin family of peptides, might be involved in various features, including increased cell proliferation, metastasis and medical treatment resistance. In this context, the objective of this paper is to explore the potential therapeutic benefits of reduced APs evolvability against cancer. Notably, the same APs are involved in the pathogenesis of neurodegenerative disease and cancer. Given the unsatisfactory outcomes of recent clinical trial of Aß immunotherapy in Alzheimer's disease, it is possible that suppressing the aggregation of individual APs might also be not effective in cancer. As such, we highlight the adiponectin (APN) paradox that might be positioned upstream of AP aggregation in both neurodegenerative disease and cancer, as a common therapeutic target in both disease types. Provided that the APN paradox due to APN resistance under the diabetic conditions might promote AP aggregation, suppressing the APN paradox combined with antidiabetic treatments might be effective for the therapy of both neurodegenerative disease and cancer.

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.

Amyloid Evolvability and Cancer.

p53 and γ-synuclein are two major regulators of cancer pathogenesis that have the propensity to form amyloid-like fibrils reminiscent of those in neurodegenerative diseases. Here we propose that fibril formation by these amyloidogenic molecules reflects evolvability, an acquired epigenetic inheritance that may be involved in cancer proliferation, drug resistance, and metastasis.

Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H ß-Synuclein.

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer's disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of ß-synuclein (ßS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which ßS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H ßS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H ßS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H ßS with αS. Collectively, we predict that ßS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H ßS Tg mice. Given that stimulation of αS evolvability by P123H ßS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered ßS were involved in the pathogenesis of sporadic DLB, the P123H ßS Tg mice could be used for investigating the mechanism and therapy of DLB.

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.

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.

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.

Early manifestation of depressive-like behavior in transgenic mice that express dementia with Lewy body-linked mutant ß-synuclein.

AIM: We previously generated transgenic (Tg) mice that expressed P123H ß-synuclein (ßS), a dementia with Lewy body-linked mutant ßS. Notably, these mice recapitulated neurodegenerative features of Lewy body disease, reflected by motor dysfunction, greater protein aggregation, and memory impairment. Since recent studies suggested that non-motor symptoms, such as depression, might be manifested in the prodromal stage of Lewy body disease, the main objective of the present study was to investigate the early expression of behavior in P123H ßS Tg mice. METHODS: Nest building, locomotor activity, and depressive-like behavior were assessed using 6- to 10-month-old male and female P123H ßS Tg and wildtype mice. KEY RESULTS: P123H ßS Tg mice exhibited hyperlocomotor activity in a novel environment, a decrease in mobility time in the tail suspension test, and impairments in nest building. CONCLUSIONS: Importantly, these non-motor behaviors were manifested before the onset of motor dysfunction, suggesting that P123H ßS Tg mice could be a valid model for investigating the early phase of Lewy body disease.

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.