Isolation and propagation of bovine blood-derived macrophages using a mixed culture with bovine endothelial B46 cells.

Macrophages are innate immune cells with multiple functions such as phagocytosis, cytokine production, and antigen presentation. Since macrophages play critical roles in some bacterial infectious diseases in cattle, including tuberculosis, paratuberculosis, and brucellosis, the in vitro culturing of bovine macrophages is useful for evaluating host-pathogen interactions at the cellular and molecular levels. We have previously reported the establishment of two immortalized bovine liver sinusoidal cell lines, endothelial B46 cells and myofibroblast-like A26 cells (Cell Biology International, 40, 1372-1379, 2016). In this study, we investigated the use of these cell lines as feeder cells that support the proliferation of bovine blood-derived macrophages (BBMs). Notably, the B46 cell line efficiently acts as feeder cells for the propagation of BBMs. Compared with primary cultured vascular endothelial cells, the infinite proliferation ability of B46 cells is more beneficial for preparing confluent feeder layers. In conclusion, this study provides a simple and efficient protocol for the isolation and propagation of BBMs using a primary mixed culture of bovine whole blood with B46 feeder cells. Isolated BBMs are expected to be useful for developing in vitro models for studying the interactions between bovine pathogens and host immune cells.

Establishment and characterization of the immortalized porcine lung-derived mononuclear phagocyte cell line.

Mononuclear phagocytes (MNP), including monocytes, dendritic cells (DC), and macrophages, play critical roles in innate immunity. MNP are abundant in the lungs and contribute to host defense against airborne agents and pulmonary immune homeostasis. In this study, we isolated porcine lung-derived MNP (PLuM) from primary cultures of parenchymal lung cells and then immortalized them by transferring the SV40 large T antigen gene and porcine telomerase reverse transcriptase gene using lentiviral vectors. The established cell line, immortalized PLuM (IPLuM), expressed DC/macrophage markers; i.e., CD163, CD172a, and major histocompatibility complex class II, whereas they did not express a porcine monocyte-specific marker, CD52. The expression patterns of these cell surface markers indicate that IPLuM originate from the DC/macrophage lineage rather than the monocyte lineage. The bacterial cell wall components muramyl dipeptide and lipopolysaccharide induced the production of the interleukin-1 family of pro-inflammatory cytokines in IPLuM. Phagocytotic activity was also detected by time-lapse fluorescence imaging of live cells when IPLuM were cultured in the presence of pHrodo dye-conjugated E. coli BioParticles. It is worth noting that IPLuM are susceptible to African swine fever virus infection and support the virus' efficient replication in vitro. Taken together, the IPLuM cell line may be a useful model for investigating host-agent interactions in the respiratory microenvironments of the porcine lung.

Polymorphisms in Pattern Recognition Receptor Genes Are Associated with Respiratory Disease Severity in Pig Farms.

Reduced productivity caused by infections, particularly respiratory diseases, is a serious problem in pig farming. We have previously reported polymorphisms in porcine pattern recognition receptor genes affecting molecular functions and demonstrated that the 2197A/C polymorphism in the nucleotide-binding oligomerization domain containing 2 (NOD2) gene influences porcine circovirus 2-induced mortality. Here, we investigated how these polymorphisms affect respiratory disease-induced lesions, using samples from a slaughterhouse dealing with pigs from two farms. Lung lesions were evaluated using two scoring systems, Goodwin (GW) and slaughterhouse pleuritis evaluation system (SPES), to determine the influence of Mycoplasma hyopneumoniae (Mhp) and Actinobacillus pleuropneumoniae (App), respectively. SPES scores were significantly higher when the 1205T allele of Toll-like receptor 5 (TLR5-1205T), rather than TLR5-1205C, was present. On the farm with more severe Mhp invasion, lower GW lesion scores were significantly associated with the presence of the NOD-like receptor family pyrin domain containing 3 (NLRP3)-2906G allele; where App invasion was worse, lower SPES scores were significantly associated with the presence of the NOD2-2197C allele. Combinations of polymorphisms in pattern recognition receptor genes can therefore be utilized for breeding for resistance against respiratory diseases in pigs. DNA markers of these polymorphisms can thus be used to improve productivity by reducing respiratory diseases due to bacterial pathogens in pig livestock.

Isolation and immortalization of macrophages derived from fetal porcine small intestine and their susceptibility to porcine viral pathogen infections.

Macrophages are a heterogeneous population of cells that are present in all vertebrate tissues. They play a key role in the innate immune system, and thus, in vitro cultures of macrophages provide a valuable model for exploring their tissue-specific functions and interactions with pathogens. Porcine macrophage cultures are often used for the identification and characterization of porcine viral pathogens. Recently, we have developed a simple and efficient method for isolating primary macrophages from the kidneys and livers of swine. Here, we applied this protocol to fetal porcine intestinal tissues and demonstrated that porcine intestinal macrophages (PIM) can be isolated from mixed primary cultures of porcine small intestine-derived cells. Since the proliferative capacity of primary PIM is limited, we attempted to immortalize them by transferring the SV40 large T antigen and porcine telomerase reverse transcriptase genes using lentiviral vectors. Consequently, immortalized PIM (IPIM) were successfully generated and confirmed to retain various features of primary PIM. We further revealed that IPIM are susceptible to infection by the African swine fever virus and the porcine reproductive and respiratory syndrome virus and support their replication. These findings suggest that the IPIM cell line is a useful tool for developing in vitro models that mimic the intestinal mucosal microenvironments of swine, and for studying the interactions between porcine pathogens and host immune cells.

A specific promoter-type in ribonuclease L gene is associated with phagocytic activity in pigs.

We have previously generated Large White pigs with high immune competence using a selection strategy based on phagocytic activity (PA), capacity of alternative complement pathway, and antibody response after vaccination against swine erysipelas. In this study, to identify the genetic changes caused by the immune selection pressure, we compared gene expression and polymorphisms in the promoter region between pigs subjected to the immune selection (immune-selected pigs) and those that were not (non-selected pigs). After lipid A stimulation, using a microarray analysis, 37 genes related to immune function and transcription factor activity showed a greater than three-fold difference in expression between macrophages derived from immune-selected and non-selected pigs. We further performed a polymorphic analysis of the promoter region of the differentially expressed genes, and elucidated the predominant promoter-types in the immune-selected and non-selected pigs, respectively, in the genes encoding ribonuclease L (RNASEL), sterile α motif and histidine-aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1, signal transducer and activator of transcription 3, and tripartite motif containing 21. Analysis of the association between these promoter genotypes and the immune phenotypes revealed that the immune-selected promoter-type in RNASEL was associated with increased PA and was inherited recessively. Considering that RNASEL has been reported to be involved in antimicrobial immune response of mice, it may be possible to enhance the PA of macrophages and improve disease resistance in pig populations using RNASEL promoter-type as a DNA marker for selection.

Ligilactobacillus salivarius Strains Isolated From the Porcine Gut Modulate Innate Immune Responses in Epithelial Cells and Improve Protection Against Intestinal Viral-Bacterial Superinfection.

Previously, we constructed a library of Ligilactobacillus salivarius strains from the intestine of wakame-fed pigs and reported a strain-dependent capacity to modulate IFN-ß expression in porcine intestinal epithelial (PIE) cells. In this work, we further characterized the immunomodulatory activities of L. salivarius strains from wakame-fed pigs by evaluating their ability to modulate TLR3- and TLR4-mediated innate immune responses in PIE cells. Two strains with a remarkable immunomodulatory potential were selected: L. salivarius FFIG35 and FFIG58. Both strains improved IFN-ß, IFN-λ and antiviral factors expression in PIE cells after TLR3 activation, which correlated with an enhanced resistance to rotavirus infection. Moreover, a model of enterotoxigenic E. coli (ETEC)/rotavirus superinfection in PIE cells was developed. Cells were more susceptible to rotavirus infection when the challenge occurred in conjunction with ETEC compared to the virus alone. However, L. salivarius FFIG35 and FFIG58 maintained their ability to enhance IFN-ß, IFN-λ and antiviral factors expression in PIE cells, and to reduce rotavirus replication in the context of superinfection. We also demonstrated that FFIG35 and FFIG58 strains regulated the immune response of PIE cells to rotavirus challenge or ETEC/rotavirus superinfection through the modulation of negative regulators of the TLR signaling pathway. In vivo studies performed in mice models confirmed the ability of L. salivarius FFIG58 to beneficially modulate the innate immune response and protect against ETEC infection. The results of this work contribute to the understanding of beneficial lactobacilli interactions with epithelial cells and allow us to hypothesize that the FFIG35 or FFIG58 strains could be used for the development of highly efficient functional feed to improve immune health status and reduce the severity of intestinal infections and superinfections in weaned piglets.

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.

An immortalized porcine macrophage cell line competent for the isolation of African swine fever virus.

African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), a fatal hemorrhagic disease of domestic pigs and wild boar. The virus primarily infects macrophage and monocyte host cells, these do not grow in vitro. Many attempts have been made to establish sustainable ASFV-sensitive cell lines, but which supported only low viral replication levels of limited, mostly artificially attenuated strains of ASFV. Here, we examined the competence of a novel cell line of immortalized porcine kidney macrophages (IPKM) for ASFV infection. We demonstrated that IPKM cells can facilitate high levels (> 107.0 TCID50/mL) of viral replication of ASFV, and hemadsorption reactions and cytopathic effects were observed as with porcine alveolar macrophages when inoculated with virulent field isolates: Armenia07, Kenya05/Tk-1, and Espana75. These results suggested that IPKM may be a valuable tool for the isolation, replication, and genetic manipulation of ASFV in both basic and applied ASF research.

Dexamethasone enhances CD163 expression in porcine IPKM immortalized macrophages.

In our previous study, we established a unique porcine macrophage cell line, immortalized porcine kidney-derived macrophages (IPKM). The purpose of the present study was to further elucidate the characteristics of IPKM. CD163 is a scavenger receptor for the hemoglobin-haptoglobin complex and is used as a phenotypic marker of anti-inflammatory M2 macrophages. The expression of CD163 is enhanced by dexamethasone (DEX), a potent steroidal anti-inflammatory drug, in human and rodent macrophages in vitro. Therefore, we investigated the effects of DEX on CD163 expression in porcine IPKM. Treatment with DEX markedly enhanced CD163 expression in the IPKM. In addition, we found that SB203580, a selective inhibitor of p38 mitogen-activated protein kinase (MAPK), blocked the effects of DEX, suggesting that the p38 MAPK signaling pathway is involved in the regulation of the DEX-induced enhancement of CD163 expression. Since CD163 is considered to be a putative receptor for the porcine reproductive and respiratory syndrome virus (PRRSV), the effects of DEX on the infection of IPKM by PRRSV were evaluated. Although the IPKM were susceptible to infection by the Fostera PRRSV vaccine strain, DEX treatment did not affect the propagation of the virus in the IPKM. This suggests that the DEX-induced enhancement of CD163 expression alone is not sufficient to facilitate the infection of IPKM by PRRSV.

Susceptibility of immortalized porcine kidney macrophages to porcine reproductive and respiratory syndrome virus-2 infection.

Porcine reproductive and respiratory syndrome virus (PRRSV) displays restricted tropism to porcine alveolar macrophages in nature. Meanwhile, non-porcine cell lines derived from African green monkey kidney cell lines are permissive to PRRSV, resulting in their widespread use in PRRSV research. Furthermore, genetically modified cell lines expressing receptors targeted by PRRSV have been established. We previously established porcine immortalized kidney-derived macrophages (IPKMs) that maintained typical macrophage function. In the present study, we demonstrated the advantages of IPKMs for PRRSV research. IPKMs expressed receptors for PRRSV such as CD163 and CD169. The efficiency of virus isolation from field biological samples was higher for IPKMs than for MARC-145 cells. Five different clusters of North American type PRRSV were propagated in IPKMs. Four field strains continuously produced progeny viruses during 10 continuous passages. The efficiency of virus isolation from field biological samples and continuous progeny virus production in the sequential passages using IPKMs indicated that these cells are good vessels for PRRSV research.

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.

Mesencephalic astrocyte-derived neurotrophic factor is a novel radioresistance factor in mouse B16 melanoma.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor produced in response to endoplasmic reticulum (ER) stress induced by various stressors, but its involvement in the radioresistance of tumor cells is unknown. Here, we found that MANF is released after γ-irradiation (2 Gy and 4 Gy) of B16 melanoma cells, and its release was suppressed by 4-phenylbutyric acid, an ER stress inhibitor. MANF was not released after low-dose (1 Gy) γ-irradiation, but pretreatment of 1 Gy-irradiated cells with recombinant MANF enhanced the cellular DNA damage response and attenuated reproductive cell death. In MANF-knockdown cells, the DNA damage response and p53 activation by γ-irradiation (2 Gy) were suppressed, and reproductive cell death was increased. MANF also activated the ERK signaling pathway. Our findings raise the possibility that MANF could be a new target for overcoming radioresistance.

Synergistic induction of drug-metabolizing enzymes in co-cultures of bovine hepatocytic and sinusoidal cell lines.

Hepatocyte-derived cell lines provide useful experimental systems for studying liver metabolism. Unlike human and rodents, few hepatocyte-derived cell lines have been generated from cattle. Here, we established two immortalized bovine hepatocyte-derived cell lines (BH4 and BH5) via transfection with a SV40 large T-antigen construct. Morphological and immunocytochemical analyses revealed that BH4 and BH5 originated from hepatocytes and biliary-epithelial cells, respectively. A potent carcinogen, 3-methylcholanthrene (3-MC), upregulated gene expression of cytochrome P450 (CYP)1A1, CYP1A2, and CYP1B1 in BH4 and BH5, but only to levels less than one-fifteenth of those in primary cultured bovine hepatocytes. Phenobarbital (PB) also increased expression levels of CYP2B6, CYP2C18, and CYP3A4 in BH4 and BH, but at a lower level than 3-MC. By contrast, when BH4 or BH5 was co-cultured with previously established bovine liver sinusoidal cell lines and treated with 3-MC, the gene expression levels of CYP1A1, CYP1A2, and CYP1B1 increased by 38~290%, compared with those in BH4 or BH5 cells cultured alone. PB-treated co-cultures of BH4 or BH5 cells and liver sinusoidal cell lines also showed synergistic increases in CYP2B6 and CYP2C18 expression. Together, the results suggest that these co-cultures could provide an in vitro model for investigations into pharmacological and toxicological properties of drugs in cattle liver.

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.

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.