scholarly journals Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

2018 ◽  
Author(s):  
Nhi Hin ◽  
Morgan Newman ◽  
Jan Kaslin ◽  
Alon M. Douek ◽  
Amanda Lumsden ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stress Responses ◽  
Early Onset ◽  
Genetic Model ◽  
Brain Aging ◽  
Zebrafish Model ◽  
Oxidative Stresses ◽  
Brain Transcriptome ◽  
The Brain

AbstractAlzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽  
2012 ◽  
Vol 25 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Katja Franke ◽  
Christian Gaser
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Elderly Subjects ◽  
Additional Increase ◽  
Longitudinal Changes ◽  
Novel Method ◽  
The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

scholarly journals Mechanisms of Brain Aging Regulation by Insulin: Implications for Neurodegeneration in Late-Onset Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Artur F. Schuh ◽  
Carlos M. Rieder ◽  
Liara Rizzi ◽  
Márcia Chaves ◽  
Matheus Roriz-Cruz
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Brain Aging ◽  
Late Onset ◽  
Energy Deficit ◽  
Insulin Degrading Enzyme ◽  
Microvascular Endothelium ◽  
Chronic Hyperglycemia ◽  
The Brain

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation.

scholarly journals Conserved Architecture of Brain Transcriptome Changes between Alzheimer’s Disease and Progressive Supranuclear Palsy in Pathologically Affected and Unaffected Regions

2021 ◽  
Author(s):  
Xue Wang ◽  
Mariet Allen ◽  
Joseph S. Reddy ◽  
Minerva M. Carrasquillo ◽  
Yan W. Asmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Neurodegenerative Disorders ◽  
Transcriptomic Data ◽  
Brain Transcriptome ◽  
Transcriptional Changes ◽  
The Brain

AbstractWe identify a striking correlation in the directionality and magnitude of gene expression changes in brain transcriptomes between Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Further, the transcriptome architecture in AD and PSP is highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and “unaffected” areas of the brain. These data have broad implications for interpreting transcriptomic data in neurodegenerative disorders.

Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

2005 ◽  
Vol 33 (5) ◽  
pp. 1041-1044 ◽  
Author(s):  
G.J. Biessels ◽  
L.J. Kappelle
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Type Ii Diabetes ◽  
Brain Aging ◽  
Building Blocks ◽  
Type Ii ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
The Brain

Type II diabetes mellitus (DM2) is associated with an increased risk of cognitive dysfunction and dementia. The increased risk of dementia concerns both Alzheimer's disease and vascular dementia. Although some uncertainty remains into the exact pathogenesis, several mechanisms through which DM2 may affect the brain have now been identified. First, factors related to the ‘metabolic syndrome’, a cluster of metabolic and vascular risk factors (e.g. dyslipidaemia and hypertension) that is closely linked to DM2, may be involved. A number of these risk factors are predictors of cerebrovascular disease, accelerated cognitive decline and dementia. Secondly, hyperglycaemia may be involved, through adverse effects of potentially ‘toxic’ glucose metabolites on the brain and its vasculature. Thirdly, insulin itself may be involved. Insulin can directly modulate synaptic plasticity and learning and memory, and disturbances in insulin signalling pathways in the periphery and in the brain have recently been implicated in Alzheimer's disease and brain aging. Insulin also regulates the metabolism of β-amyloid and tau, the building blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer's disease. In this paper, the evidence for the association between DM2 and dementia and for each of these underlying mechanisms will be reviewed, with emphasis on the role of insulin itself.

scholarly journals Prediction of Alzheimer’s Disease Based on Coordinate-Dense Attention Network

2021 ◽  
Author(s):  
Yongmei Tang ◽  
Xiangyun Liao ◽  
Weixin Si ◽  
Zhigang Ning
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Changes ◽  
Brain Aging ◽  
Significant Feature ◽  
Convolutional Network ◽  
Basic Model ◽  
Prediction Scheme ◽  
Feature Information ◽  
The Brain

Alzheimer’s disease (AD) is a degenerative disease of the nervous system. Mild cognitive impairment (MCI) is a condition between brain aging and dementia. The prediction will be divided into stable sMCI and progressive pMCI as a binary task. Structural magnetic resonance imaging (sMRI) can describe structural changes in the brain and provide a diagnostic method for the detection and early prevention of Alzheimer’s disease. In this paper, an automatic disease prediction scheme based on MRI was designed. A dense convolutional network was used as the basic model. By adding a channel attention mechanism to the model, significant feature information in MRI images was extracted, and the unimportant features were ignored or suppressed. The proposed framework is compared with the most advanced methods, and better results are obtained.

scholarly journals Cornel iridoid glycoside ameliorated Alzheimer's disease-like pathologies and necroptosis through RIPK1/MLKL pathway in young and aged SAMP8 mice

2021 ◽  
Author(s):  
Denglei Ma ◽  
Yanzheng Li ◽  
Yanqiu Zhu ◽  
Weipeng Wei ◽  
Li Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Aging ◽  
Neuronal Loss ◽  
Iridoid Glycoside ◽  
Intragastric Administration ◽  
Cornel Iridoid Glycoside ◽  
Samp8 Mice ◽  
The Brain

Abstract Background Aging is an important risk factor for sporadic Alzheimer’s disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD researches. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. Methods Nissl and immunohistochemical staining was applied to detect NeuN-labeled neurons and myelin basic protein-labeled myelin sheath,. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing and necroptosis. Results The results showed that SAMP8 mice at the age of 6 and 14 months exhibited age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months alleviated neuronal loss and demyelination, increased the expression of synaptophysin, postsynaptic density protein 95 and AMPA receptor subunit 1, elevated the levels of soluble APPα fragment and a disintegrin and metalloproteinase 10 (ADAM10), and decreased the levels of RIPK1, p-MLKL and MLKL in the brain of young and aged SAMP8 mice. Conclusion This study denoted that CIG might be a potential drug for aging-associated neurodegenerative diseases such as AD.

scholarly journals Xueshuantong Improves Functions of Lymphatic Ducts and Modulates Inflammatory Responses in Alzheimer’s Disease Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Zheng ◽  
Yang-mei Huang ◽  
Qiang Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Inflammatory Responses ◽  
Brain Aging ◽  
Lymphatic Vessels ◽  
Amyloid Β ◽  
Brain Functions ◽  
Vital Functions ◽  
The Brain

Recent studies have revealed significant contributions of lymphatic vessels (LVs) to vital functions of the brain, especially related to clearance of waste from the brain and immune responses in the brain. These studies collectively indicate that enhancing the functions of LVs may improve brain functions during brain aging and in Alzheimer’s disease (AD) where LV functions are impaired. However, it is currently unknown whether this enhancement can be achieved using small molecules. We have previously shown that a widely used Chinese herbal medicine Xueshuantong (XST) significantly improves functions and reduces pathology in AD transgenic mice associated with elevated cerebral blood flow (CBF). Here, we show that XST partially rescues deficits in lymphatic structures, improves clearance of amyloid-β (Aβ) from the brain, and reduces the inflammatory responses in the serum and brains of transgenic AD mice. In addition, we showed that this improvement in the lymphatic system occurs independently of elevated CBF, suggesting independent modulation and limited interaction between blood circulation and lymphatic systems. Moreover, XST treatment leads to a significant increase in GLT-1 level and a significantly lower level of MMP-9 and restores AQP4 polarity in APP/PS1 mice. These results provide the basis for further exploration of XST to enhance or restore LV functions, which may be beneficial to treat neurodegenerative diseases or promote healthy aging.

Sign in / Sign up

Export Citation Format

Share Document