The discovery of insulin in 1921 revolutionized the treatment of diabetes and paved the way for numerous studies on hormone signalling networks and actions in peripheral tissues and in the central ...nervous system. Impaired insulin signalling, a hallmark of diabetes, is now established as a key component of Alzheimer disease (AD) pathology. Here, we review evidence showing that brain inflammation and activation of cellular stress response mechanisms comprise molecular underpinnings of impaired brain insulin signalling in AD and integrate impaired insulin signalling with AD pathology. Further, we highlight that insulin resistance is an important component of allostatic load and that allostatic overload can trigger insulin resistance. This bidirectional association between impaired insulin signalling and allostatic overload favours medical conditions that increase the risk of AD, including diabetes, obesity, depression, and cardiovascular and cerebrovascular diseases. Finally, we discuss how the integration of biological, social and lifestyle factors throughout the lifespan can contribute to the development of AD, underscoring the potential of social and lifestyle interventions to preserve brain health and prevent or delay AD.
Mounting evidence indicates that signaling molecules identified primarily in the peripheral circulation can affect cognitive function in physiological and pathological conditions, including in the ...development of several neurological diseases. However, considering the properties of the vascular blood-brain barrier (BBB), circulating lipophobic molecules would not be expected to cross this vascular structure. Thus, if and how peripheral lipophobic molecules, such as hormones and cytokines, reach the brain to exert their reported effects remains to be better established. In this review, we will discuss evidence for and against the ability of molecules in the circulation, such as insulin, cytokines, and irisin to reach the brain and mediate the crosstalk between peripheral tissues and the central nervous system (CNS). We hypothesize that in addition to entering the brain via receptor-mediated transcytosis, these circulating molecules can have their transport facilitated by extracellular vesicles or under pathological conditions when the BBB is disrupted. We also discuss the possibility that these circulating molecules access the brain by acting directly on circumventricular organs, which lack the BBB, by local synthesis in the choroid plexus, and via activation of afferent vagal nerves. Advancing the understanding of mechanisms implicated in the transport of blood-borne molecules to the CNS will help us elucidate the contribution of peripheral factors to brain health and disease, and will enable the development of minimally invasive strategies to deliver therapeutic drugs to the brain in neurological disorders.
This article is part of the special Issue on ‘Cross Talk between Periphery and the Brain’.
•The vascular BBB is highly selective and integrates peripheral and central signals.•Small lipophilic molecules can cross the BBB via transmembrane diffusion.•The ability of hormones and cytokines to cross the BBB remains to be fully understood.•Other mechanisms may facilitate the action of circulating hormones and cytokines in the brain.•Understanding the mechanisms of crosstalk between brain and periphery is important for the development of therapeutics.
Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on ...cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.
The rising incidence of visceral leishmaniasis due to Leishmania infantum requires novel methods to control transmission by the sand fly vector. Indoor residual spraying of insecticide (IRS) against ...these largely exophilic / exophagic vectors may not be the most effective method. A synthetic copy of the male sex-aggregation pheromone of the key vector species Lutzomyia longipalpis in the Americas, was co-located with residual pyrethroid insecticide, and tested for its effects on vector abundance, hence potential transmission, in a Brazilian community study.
Houses within eight defined semi-urban blocks in an endemic municipality in Brazil were randomised to synthetic pheromone + insecticide or to placebo treatments. A similar number of houses located >100m from each block were placebo treated and considered as "True Controls" (thus, analysed as three trial arms). Insecticide was sprayed on a 2.6m2 surface area of the property boundary or outbuilding wall, co-located within one metre of 50mg synthetic pheromone in controlled-release dispensers. Vector numbers captured in nearby CDC light traps were recorded at monthly intervals over 3 months post intervention. Recruited sentinel houses under True Control and pheromone + insecticide treatments were similarly monitored at 7-9 day intervals. The intervention effects were estimated by mixed effects negative binomial models compared to the True Control group.
Dose-response field assays using 50mg of the synthetic pheromone captured a mean 4.8 (95% C.L.: 3.91, 5.80) to 6.3 (95% C.L.: 3.24, 12.11) times more vectors (female Lu. longipalpis) than using 10mg of synthetic pheromone. The intervention reduced household female vector abundance by 59% (C.L.: 48.7, 66.7%) (IRR = 0.41) estimated by the cross-sectional community study, and by 70% (C.L.: 56.7%, 78.8%) estimated by the longitudinal sentinel study. Similar reductions in male Lu. longipalpis were observed. Beneficial spill-over intervention effects were also observed at nearby untreated households with a mean reduction of 24% (95% C.L.: 0.050%, 39.8%) in female vectors. The spill-over effect in untreated houses was 44% (95% C.L.: 29.7%, 56.1%) as effective as the intervention in pheromone-treated houses. Ownership of chickens increased the intervention effects in both treated and untreated houses, attributed to the suspected synergistic attraction of the synthetic pheromone and chicken kairomones. The variation in IRR between study blocks was not associated with inter-household distances, household densities, or coverage (proportion of total households treated).
The study confirms the entomological efficacy of the lure-and-kill method to reduce the abundance of this important sand fly vector in treated and untreated homesteads. The outcomes were achieved by low coverage and using only 1-2% of the quantity of insecticide as normally required for IRS, indicating the potential cost-effectiveness of this method. Implications for programmatic deployment of this vector control method are discussed.
Introduction
Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease ...mechanisms. Reduced brain‐derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise‐induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti‐inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined.
Methods
In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15‐item Geriatric Depression Scale (GDS‐15).
Results
CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia.
Discussion
Our findings provide novel insight into shared molecular signatures connecting depression and dementia.
INTRODUCTION
Extracellular vesicles (EVs) have been implicated in the spread of neuropathology in Alzheimer's disease (AD), but their involvement in behavioral outcomes linked to AD remains to be ...determined.
METHODS
EVs isolated from post mortem brain tissue from control, AD, or frontotemporal dementia (FTD) donors, as well as from APP/PS1 mice, were injected into the hippocampi of wild‐type (WT) or a humanized Tau mouse model (hTau/mTauKO). Memory tests were carried out. Differentially expressed proteins in EVs were assessed by proteomics.
RESULTS
Both AD‐EVs and APP/PS1‐EVs trigger memory impairment in WT mice. We further demonstrate that AD‐EVs and FTD‐EVs carry Tau protein, present altered protein composition associated with synapse regulation and transmission, and trigger memory impairment in hTau/mTauKO mice.
DISCUSSION
Results demonstrate that AD‐EVs and FTD‐EVs have negative impacts on memory in mice and suggest that, in addition to spreading pathology, EVs may contribute to memory impairment in AD and FTD.
Highlights
Aβ was detected in EVs from post mortem AD brain tissue and APP/PS1 mice.
Tau was enriched in EVs from post mortem AD, PSP and FTD brain tissue.
AD‐derived EVs and APP/PS1‐EVs induce cognitive impairment in wild‐type (WT) mice.
AD‐ and FTD‐derived EVs induce cognitive impairment in humanized Tau mice.
Proteomics findings associate EVs with synapse dysregulation in tauopathies.
Parkinson’s disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy ...bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α–syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.
This study introduces a new 3D scaffold based on thiolated chitosans with luminescence by microwave radiation using cysteine (Chi_CT_Cys) and 11-mercaptoundecanoic acid (Chi_CT_MUA) for vertebral ...disc regeneration/theragnostic. These scaffolds were characterized by Raman, PL spectroscopy, swelling, gel-fraction, and morphologies. Cytocompatibility and mechanical behavior were evaluated. Raman showed that disulfide bonds improved the grafting degree (Chi_CT_Cys (1072 ± 136) μmol·g−1 and Chi_CT_MUA (3245 ± 105) μmol·g−1). Morphologies showed interesting characteristics. Swelling behavior showed that Chi_CT_MUA presented a slight minor swelling (2101 ± 251) % compared to Chi_CT_Cys (2589 ± 188) %. Differently, gel-fraction showed that the chemical stability of Chi_CT_Cys was worse (29 ± 4) % than Chi_CT_MUA (15 ± 3) %. PL showed a possibility to use theragnostic evaluation of points of greater compression in a vertebral disc. The mechanical behavior of Chi_CT_MUA presented better results ((70 ± 3) MPa) than Chi_CT_Cys ((37 ± 3) MPa). Cytocompatible showed that the scaffolds presented cell viability >90%. Thusly, these 3D scaffolds presented an incredible potential for tissue engineering applications.
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•New 3D scaffold-based on thiolated chitosan prepared rapidly using microwave radiation.•3D Scaffolds were prepared via a simple green and efficient route.•Different grafting depending on the thiol-modifier promote improvement in fluorescence.•Biocompatible 3D scaffold presented a highly porous and outstanding mechanical performance.•The new 3D scaffolds are potential for applications in soft tissue engineering for repair and theragnostic.
HPV-16 driven oropharynx/oral cavity squamous cell carcinomas prevalence varies globally. We evaluated the presence of HPV-16 ctDNA and HPV-16 E6 antibodies in samples obtained from participants ...treated at the Instituto do Cancer do Estado de Sao Paulo, ICESP, and from whom tumoral HPV DNA, HPV-16 E6*I mRNA, and p16
status was also accessed.
HPV was genotyped by PCR-hybridization. All HPV DNA positive and ∼10 % HPV DNA negative cases underwent p16
immunohistochemistry and E6*I RNA testing using a multiplex bead based protocol. HPV-16 ctDNA and anti-E6 antibodies were assessed by ddPCR (digital droplet PCR) and multiplex serology, respectively.
The prevalence of HPV-16 in oropharynx carcinoma (OPC) cases was low (8.7 %) when considering solely HPV-16 DNA detection, and even lower (5.2 %) when taken into consideration the concomitant detection of HPV-16 E6*I RNA and/or p16
(HPV-16 attributable fraction - AF). None of the oral cavity cancer (OCC) cases were detected with HPV-16 DNA. HPV-16 ctDNA was more commonly detected than HPV-16 E6 antibodies (29.8 % versus 10.6 %). Both serum biomarkers attained 100 % sensitivity of detecting HPV-16 AF OPC, however the specificity of the HPV-16 anti-E6 biomarker was higher compared to ctDNA (93.2 % versus 75.0 %). Finally, when both HPV-16 ctDNA and anti-E6 biomarkers were considered together, the sensitivity and specificity for HPV-16 OPC detection was 100 % and about 70 %, respectively, independently of analyzing HPV-16 DNA positive or HPV-16 AF tumors.
Our findings corroborate that serum biomarkers are highly sensitive and specific biomarkers for detection of HPV-associated OPC.
INTRODUCTION
We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within ...neurodegenerative diseases.
METHODS
Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p‐tau)181 and amyloid beta (Aβ)42/40 were measured using ultra‐sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD).
RESULTS
GFAP, NfL, and/or p‐tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p‐tau181 were highly predictive across diseases, p‐tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40.
DISCUSSION
GFAP, NfL, and p‐tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.
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