The history of Lake Maggiore industrial pollution traced through lake sediment and long term monitoring of the biota

In Lake Maggiore large watershed (ca. 6,600 sq. km), industrial activities along the XX century led to the discharge into the lake or its tributaries of several pollutants, such as DDT, PCBs and mercury. Other pollutants, such as PAHs and flame retardants (such as PBDEs) are still reaching the lake. Analyses of some of these pollutants in lake biota were performed continuously since 1998 and form a unique time series. We used in parallel lake sediment cores to infer the history of lake contamination, and analyses of biological samples to describe the distribution of these pollutants in the lake food web and its year-to-year variability. Furthermore, analysis of the sediment of the main rivers flowing towards Lake Maggiore was used to get information on present sources of pollution. Results also show that legacy pollutants, which are no more used nor produced, still reach the lake from polluted soils located around the industrial sites, in particular during heavy rainfall. In particular, we paid special attention to Hg and to DDT and its metabolites, because of the presence of a large pollution source close to the River Toce, one of the main inlets of Lake Maggiore. Although DDT production ended in 1996, p,p\u27-DDT is still found in river sediment and in molluscs collected in Lake Maggiore, deriving probably from polluted soils. On the contrary, p,p\u27-DDE prevails in fish tissues, zooplankton and molluscs. Finally, high values of the concentration of some pollutants in the sediment of Lake Maggiore outlet (River Ticino) show that the lake does not act as a perfect sink for these compounds. Considering present day pollution, PAHs derive from diffuse sources and are found in the sediment of all tributaries, while PBDEs where found only in the sediment of two inlets, revealing the presence of active point sources

WAT ALTERATIONS IN DIABETIC MICE: ITS CONNECTION AND IMPLICATION IN AD PATHOGENESIS

Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses associated with white adipose tissue expansion, are risk factors for AD. Here, we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses. We used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from WT and db/db mice. Moreover, similar techniques were used in the brain of 3xTg-AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology. Our study shows that recipient 3xTg-AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5/p25 expression compared to 3xTg-AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL-1β and microglial activation. However, we found that Aβ levels were reduced in recipient 3xTg-AD mice from db/db fat pads compared to 3xTg- AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity. Overall, our study demonstrates a novel important crosstalk between AD and diabetes type II through white adipose cells and a differential effect on tau and Aβ pathology

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood–brain barrier to reach the target areas in the brain or to regulate the function of the blood–brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood–brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential.Funding for open access charge; Universidad de Málaga / CBU

Human amyloid seeds aggregate more efficient than seeds from old 3xtg-ad mice

Aims: Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in animal models show that the injection of brain homogenates from AD patients or from aged APP-transgenic mice containing Aβ aggregates, can induce some of the neuropathological hallmarks of AD. However, it is still unknown which Aβ-misfolded species are most efficient in triggering the aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) is more efficient to generate amyloid aggregates. Methods: We employed histological and molecular approaches to determine amyloid level, species and aggregative capacity of brain homogenates from an AD patient (stage C for amyloid, from the Alzheimer’s Disease Research Center at UCI) vs old-3xTg-AD mice (25-month-old). Such brain homogenates were injected into the hippocampus of 7-month-old 3xTg-AD mice and the mice were analyzed at 18 months of age. Results: Our findings demonstrated that amyloid seeds from the human patient have more capacity to generate Aβ plaques vs seeds from aged 3xTg-AD mice. Conclusions: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Impact of white adipose tissue in AD pathology

Introduction: Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences has suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. In addition, novel studies has suggested that AD induces peripheral metabolic alterations, facilitating the development of diabetes. Overall, these studies suggest that there is an important two-way crosstalk between AD and peripheral metabolic disorders. Here, we seek to understand the mechanisms underlying this association and we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and alterations in this organ may affect both types of disorders. Methods: Here, we used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from wt and 3xTg-AD mice. Moreover, similar techniques were used in the brain of 3xTg-AD mice that received white fat pads from wt and 3xTg-AD donors to determine any changes in amyloid and tau pathology. Results: Our study shows that 3xTg-AD mice develop significant peripheral metabolic alterations which in turn affected the white adipose tissue biology. Moreover, adipose tissue transplanted from donor 3xTg-AD and wt mice into recipient 3xTg-AD mice indicate that AD associated white fat tissue induced profound AD pathology changes in recipient 3xTg-AD mice. Conclusions: Overall, our study demonstrate a novel important crosstalk between AD and peripheral metabolic disorders thought white adipose cells. A more profound understanding in these processes may turn in novel and promising therapeutic strategies for AD and metabolic illnesses.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Visceral adipose tissue triggers tau pathogenesis in transgenic mice

Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders. Method: We used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg-AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology. Result: Our study shows that recipient 3xTg-AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg-AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL-1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg-AD mice from db/db fat pads compared to 3xTg-AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity. Conclusion: Overall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.This study was supported by Minister of Science and Innovation grant PID2019-108911RA-100 (D.B.V.), Alzheimer's Association grant AARG-22-9282/9, Beatriz Galindo program BAGAL18/00052 (D.B.V.), University of Malaga grant PPIT.UMA.B1- 2021_32(LTE) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) cofinanced by FEDER funds from European Union

Human and mouse seeds differentially affect AB aggregation by modulating the inflammatory response.

Abstract text: Alzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prionlike process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process. Methods: Amyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo-3xTg-AD mice were injected into the hippocampus of 7-8- month-old 3xTg-AD mice. They were analyzed 10 months post-surgery for amyloid and microglia markers. Results: Our findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. Moreover, human and mice seeds differentially affect the presence of plaque-associated microglia in 3xTgAD mice. Conclusion: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key insight on how amyloid pathology progresses in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Visceral adipose tissue triggers tau pathogenesis in transgenic mice through CDK5/P25 pathway.

Alzheimer’s disease (AD) is a complex disorder and multiple molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in this disease progression. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue (VAT). Here, we hypothesize that the VAT may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders. We used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg-AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology. Our study shows that recipient 3xTg-AD mice from db/db mice fat pads develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg-AD mice that received fat pads from WT mice. This increment in tau level was associated with elevated levels in IL-1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg-AD mice from db/db fat pads compared to 3xTg-AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity. Overall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Amyloid propagation in a sporadic model of Alzheimer disease

Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in FAD-based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP-transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ-seeding studies have been done in APP-transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition. Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD mice were employed. Our findings demonstrated that amyloid seeds differentially occur in 3xTg-AD and hAb-KI mice and these aggregates are developed earlier in the familial model, 3xTg-AD mice. These results suggest that multiple factors such as the seed, recipient model and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Human and mouse seeds differentially affect Aβ aggregation by modulating the inflammatory response

Background: Alzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process. Method: Amyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo-3xTg-AD mice were injected into the hippocampus of 7-8-month-old 3xTg-AD mice. They were analyzed 10 months postsurgery for amyloid and microglia markers. Result: Our findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. Moreover, human and mice seeds differentially affect the presence of plaqueassociated microglia in 3xTg-AD mice. Conclusion: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key insight on how amyloid pathology progresses in AD.This study was supported by Minister of Science and Innovation grant PID2019-108911RA-100 (D.B.V.), Alzheimer’s Association grant AARG-22-928219 (D.B.V), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co-financed by FEDER funds from European Union