scholarly journals COMPLEMENT CONTRIBUTES TO ALZHEIMER’S DISEASE-INDUCED SYNAPSE DECLINE IN THE MURINE RETINA

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S967-S967
Author(s):  
Fenge Li ◽  
Danye Jiang ◽  
Melanie Samuel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Horizontal Cell ◽  
Brain Dysfunction ◽  
Cell Integrity ◽  
Rt Pcr ◽  
Aged Patients ◽  
Complement Component C3 ◽  
Cell Processes ◽  
Ad Mouse Model

Abstract Alzheimer's disease (AD) is among the most debilitating form of cognitive impairment in aged patients. Synapse deficits are thought to be a central trigger of neural miswiring and brain dysfunction in AD. However, the pathways that control synapse connectivity remain largely unknown. The retina is an easily accessible system with two distinct synapse layers and three cellular layers comprised of distinct neural types. In this study, we leveraged this system to assess synapse and cell integrity in the APPNLGF amyloid-beta AD mouse model. We showed that the expression of the complement component C3 is significantly increased in APPNLGF retina synapses, and that there is a significant decline of several synapse-associated markers by RT-PCR. These mice also display disorganized horizontal cell processes and visual function deficits. These results suggest that complement may drive AD-related changes in the synaptic and functional properties of the retina, which could serve as assessable preclinical biomarkers for AD. In ongoing studies, we are testing whether and how complement regulates synapse refinement and shapes retina synapse specificity in AD.

scholarly journals Mathematical analysis of the influence of brain metabolism on the BOLD signal in Alzheimer’s disease

2017 ◽  
Vol 38 (2) ◽  
pp. 304-316 ◽  
Author(s):  
Felix Winter ◽  
Catrin Bludszuweit-Philipp ◽  
Olaf Wolkenhauer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Resting State Fmri ◽  
Blood Oxygen Level Dependent ◽  
Peak Height ◽  
Brain Dysfunction ◽  
Patient Specific ◽  
Theoretic Approach ◽  
Hemodynamic Response Function ◽  
Clinical Tool

Blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) is a standard clinical tool for the detection of brain activation. In Alzheimer’s disease (AD), task-related and resting state fMRI have been used to detect brain dysfunction. It has been shown that the shape of the BOLD response is affected in early AD. To correctly interpret these changes, the mechanisms responsible for the observed behaviour need to be known. The parameters of the canonical hemodynamic response function (HRF) commonly used in the analysis of fMRI data have no direct biological interpretation and cannot be used to answer this question. We here present a model that allows relating AD-specific changes in the BOLD shape to changes in the underlying energy metabolism. According to our findings, the classic view that differences in the BOLD shape are only attributed to changes in strength and duration of the stimulus does not hold. Instead, peak height, peak timing and full width at half maximum are sensitive to changes in the reaction rate of several metabolic reactions. Our systems-theoretic approach allows the use of patient-specific clinical data to predict dementia-driven changes in the HRF, which can be used to improve the results of fMRI analyses in AD patients.

scholarly journals Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling

2020 ◽  
Vol 11 (1) ◽  
pp. 391-401
Author(s):  
Jiang Cheng ◽  
Guowei Wang ◽  
Na Zhang ◽  
Fang Li ◽  
Lina Shi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
The Elderly ◽  
Tnf Α ◽  
Autophagic Process ◽  
Molecular Signals ◽  
Ad Mouse Model ◽  
Mtor Signalling

AbstractBackground:Alzheimer’s disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model.Methods:Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer’s mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort.Results:The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes – including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) – via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107.Conclusion:This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.

scholarly journals Fingolimod Rescues Memory and Improves Pathological Hallmarks in the 3xTg-AD Model of Alzheimer’s Disease

2022 ◽  
Author(s):  
Steven G. Fagan ◽  
Sibylle Bechet ◽  
Kumlesh K. Dev
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biochemical Analysis ◽  
Spatial Working Memory ◽  
Cell Number ◽  
Model Of Alzheimer’S Disease ◽  
Candidate Drug ◽  
Inflammatory Processes ◽  
The Brain ◽  
Ad Mouse Model

AbstractTherapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.

Structural, Functional, and Molecular Neuroimaging Biomarkers for Alzheimer’s Disease

2013 ◽  
pp. 821-825
Author(s):  
James B. Brewer ◽  
Jorge Sepulcre ◽  
Keith A. Johnson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Brain Dysfunction ◽  
Imaging Biomarkers ◽  
Neurocognitive Evaluation ◽  
Neuroimaging Biomarkers

Advances in quantitative structural, functional, and molecular neuroimaging have provided new tools for objective, in vivo, assessment of critical aspects of Alzheimer’s disease and other neurodegenerative disorders. Measures of brain atrophy or brain dysfunction, coupled with measures of disease-linked pathology, might complement the history, physical and neurocognitive evaluation of patients and thereby improve predictive prognosis, especially at early stages of cognitive impairment where neurodegenerative etiology is less certain. Such imaging biomarkers are currently used in nearly all clinical trials of therapeutic agents for Alzheimer’s disease and are increasingly incorporated into clinical practice. In this chapter, imaging biomarkers are introduced and discussed to familiarize the reader with their potential research and clinical uses.

scholarly journals Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Siddhartha Mondragón-Rodríguez ◽  
Humberto Salgado-Burgos ◽  
Fernando Peña-Ortega
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Network Connectivity ◽  
Aspartate Receptor ◽  
Potential Biomarker ◽  
Prodromal Ad ◽  
Brain Circuit ◽  
New Evidence ◽  
Ad Mouse Model

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease

Life Sciences ◽  
2014 ◽  
Vol 116 (2) ◽  
pp. 83-89 ◽  
Author(s):  
E. Orta-Salazar ◽  
A. Aguilar-Vázquez ◽  
H. Martínez-Coria ◽  
S. Luquín-De Anda ◽  
M. Rivera-Cervantes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Expression ◽  
Induced Changes ◽  
Ad Mouse Model

scholarly journals Altered slow (<1 Hz) and fast (beta and gamma) neocortical oscillations in the 3xTg-AD mouse model of Alzheimer's disease under anesthesia

2019 ◽  
Vol 79 ◽  
pp. 142-151 ◽  
Author(s):  
Patricia Castano-Prat ◽  
Lorena Perez-Mendez ◽  
Maria Perez-Zabalza ◽  
Coral Sanfeliu ◽  
Lydia Giménez-Llort ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Ad Mouse Model

scholarly journals Perivascular Nerves of the Human Basal Cerebral Arteries: II. Changes in Aging and Alzheimer's Disease

1996 ◽  
Vol 16 (5) ◽  
pp. 1048-1057 ◽  
Author(s):  
Ronald L. A. W. Bleys ◽  
Tim Cowen ◽  
Gerbrand J. Groen ◽  
Berend Hillen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Artery ◽  
Cerebral Arteries ◽  
Aged Patients ◽  
Protein Gene Product ◽  
Perivascular Nerves ◽  
Intrinsic Nerve ◽  
Anterior Choroidal ◽  
Cryostat Sections

In the present study the intrinsic nerve plexuses of the basal cerebral arteries, derived from aged non-Alzheimer's and aged Alzheimer's disease patients were quantified and compared. A previous study described and quantified nerve density on similar arteries from healthy middle-aged patients. Whole-mount preparations of various segments of the basal cerebral arteries were stained for protein gene product 9.5. The deep nerve plexuses, located at the adventitial–medial border, were quantified by image analysis. Transverse cryostat sections were stained for various markers and quantified. Measurements on whole mounts demonstrated that nerve densities were highest in the posterior communicating artery and in the postcommunicating part of the posterior cerebral artery (PCA) for both aged and Alzheimer's groups. Statistical comparison showed a tendency toward decreased nerve density with aging, which was significant for the internal carotid artery, precommunicating part of the PCA, and the anterior choroidal artery in both non-Alzheimer's and Alzheimer's aged groups. In addition, in Alzheimer's patients nerve density was significantly lower in the precommunicating part of the anterior cerebral artery compared with the healthy aged group. Measurements on sections confirmed the tendency to decreased innervation with aging. It is concluded that densities of deep perivascular nerves of human basal cerebral arteries are subject to localized changes caused by aging and Alzheimer's disease.

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