Change in weight and waist circumference and risk of colorectal cancer: Results from the Melbourne Collaborative Cohort Study

Background: Studies reporting the association between change in weight or body mass index during midlife and risk of colorectal cancer have found inconsistent results, and only one study to date has reported the association between change in waist circumference (a measure of central adiposity) and risk of colorectal cancer. Methods: We investigated the association between risk of colorectal cancer and changes in directly measured waist circumference and weight from baseline (1990-1994) to wave 2 (2003-2007). Cox regression, with age as the time metric and follow-up starting at wave 2, adjusted for covariates selected from a causal model, was used to estimate the Hazard Ratios (HRs) and 95 % Confidence Intervals (CIs) for the change in waist circumference and weight in relation to risk of colorectal cancer. Results: A total of 373 cases of colorectal cancer were diagnosed during an average 9 years of follow-up of 20,605 participants. Increases in waist circumference and weight were not associated with the risk of colorectal cancer (HR per 5 cm increase in waist circumference = 1.02; 95 % CI: 0.95, 1.10; HR per 5 kg increase in weight = 0.93; 0.85, 1.02). For individuals with a waist circumference at baseline that was less than the sex-specific mean value there was a slight increased risk of colorectal cancer associated with a 5 cm increase in waist circumference at wave 2 (HR = 1.08; 0.97, 1.21). Conclusion: Increases in waist circumference and weight during midlife do not appear to be associated with the risk of colorectal cancer

Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort

Background: While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk. Methods and Findings: We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD. Conclusions: Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms. Please see later in the article for the Editors' Summar

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling batterThis research was funded by INSTITUTO DE SALUD CARLOS III (ISCiii) of Spain, cofinanced by FEDER funds from European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by JUNTA DE ANDALUCIA CONSEJERÍA DE ECONOMÍA Y CONOCIMIENTO through grants UMA18-FEDERJA-211 (to AG), UMA20-FEDERJA-104 (to IMG), P18-RT-2233 (to AG) and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020 and CONSEJERIA DE SALUD grant PI-0276-2018 (to JAGL); by SPANISH MINISTER OF SCIENCE AND INNOVATION grant PID2019-108911RA-100 (to DBV), BEATRIZ GALINDO PROGRAM BAGAL18/00052 (to DBV), Alzheimer Association AARG-22-928219 (to DBV), grant PID2019-107090RA-100 (to IMG) and RAMON Y CAJAL PROGRAM RYC-2017-21879 (to IMG); and by MALAGA UNIVERSITY grant B1-2019_07 (to ESM), grant B1-2020_04 (to JAGL), grant B1-2019_06 (to IMG) and NASARD grant 27565 2018 (to IMG). M.M.-O. held a predoctoral contract from Malaga University, J.J.F.-V. held a postdoctoral contract from Malaga University, and E.S.-M. a postdoctoral contract (DOC_00251) from Junta de Andalucia. Partial funding for open access charge: Universidad de Málaga

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

Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/ APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Ab oligomers were identified, the presence of A11-immunopositive Ab plaques also suggested a direct role of plaque-associated Ab oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.Fondo de Investigación Sanitaria (FIS). Instituto de Salud Carlos III, España. PS09/00099, PS09/00151, PS09/00848 y PS09/00376Junta de Andalucía. SAS P09/496 y CTS-479

Amyloid-b seeding and propagation processes in a hAb-KI model of Alzheimer's disease

Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process. Several studies using FAD animal models have demonstrated that intracerebral infusion of brain extracts from APP-transgenic mice or AD patients induce Aβ deposition and cerebral amyloid angiopathy. To carry out most of these Aβ-seeding studies, APP-transgenic animal have been used. Nevertheless, it remains to be elucidated whether Aβ deposition can be induced by Aβ-seeds in a sporadic AD model that does not overexpress APP and produces wild type human Aβ. We used an innovative model to better understand the amyloidogenic events that occur in sporadic AD. This hAβ-KI model, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. Aβ-seeds from AD patients (stage C) from the AD Research Center (UCI) were administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD mice were employed. We demonstrated that amyloid seeds can stimulate Aβ aggregations in 3xTg-AD and hAβ-KI models. We found that Aβ aggregates occur earlier in the 3xTg-AD vs hAβ-KI and that a longer term of treatment is necessary to accelerate diffusible Aβ pathology in the hAβ-KI mice. Thereferoe, this hAβ-KI model represents an important step towards the development of next-generation animal models that will provide better predictive outcomes for human patients. Grants support: UCI MIND Pilot project (DBV), Ministry of Science PID2019-108911RA-100 (DBV), U54 AG054349 (FML), Institute of Health Carlos III PI18/01557 (AG) co-financed by FEDER funds (European Union), NIH/NIA Grant P50 AG16573 (UCI-ADRC).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.This study was supported by the Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by the FEDER funds from European Union, through grants PI18/01557 (to AG) and PI18/01556 (to JV); by the Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 (to AG), P18-RT-2233 (to AG), and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020; by the Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DB-V), Beatriz Galindo program BAGAL18/00052 (to DB-V) grant PID2019-107090RA-I00 (to IM-G), and Ramon y Cajal Program RYC-2017-21879 (to IM-G); and by the Malaga University grants B1-2019_07 (to ES-M) and B1-2019_06 (to IM-G). MM-O held a predoctoral contract from Malaga University and ES-M a postdoctoral contract (DOC_00251) from Junta de Andalucia