scholarly journals Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

2019 ◽  
Author(s):  
Jessica L. Hoffman ◽  
Sara Faccidomo ◽  
Michelle Kim ◽  
Seth M. Taylor ◽  
Abigail E. Agoglia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Alcohol Use ◽  
Entorhinal Cortex ◽  
Alcohol Drinking ◽  
Alcohol Exposure ◽  
The United States ◽  
The Impact ◽  
Behavioral Pathology

ABSTRACTAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that non-dependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, 2-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wildtype mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer’s pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

scholarly journals The Impact of Experience with a Family Member with Alzheimer’s Disease on Views about the Disease across Five Countries

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Robert J. Blendon ◽  
John M. Benson ◽  
Elizabeth M. Wikler ◽  
Kathleen J. Weldon ◽  
Jean Georges ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Family Member ◽  
Public Spending ◽  
The United States ◽  
Direct Experience ◽  
Fatal Disease ◽  
The Public ◽  
Educational Campaigns ◽  
The Impact

The objective of this paper is to understand how the public’s beliefs in five countries may change as more families have direct experience with Alzheimer’s disease. The data are derived from a questionnaire survey conducted by telephone (landline and cell) with 2678 randomly selected adults in France, Germany, Poland, Spain, and the United States. The paper analyzes the beliefs and anticipated behavior of those in each country who report having had a family member with Alzheimer’s disease versus those who do not. In one or more countries, differences were found between the two groups in their concern about getting Alzheimer’s disease, knowledge that the disease is fatal, awareness of certain symptoms, and support for increased public spending. The results suggest that as more people have experience with a family member who has Alzheimer’s disease, the public will generally become more concerned about Alzheimer’s disease and more likely to recognize that Alzheimer’s disease is a fatal disease. The findings suggest that other beliefs may only be affected if there are future major educational campaigns about the disease. The publics in individual countries, with differing cultures and health systems, are likely to respond in different ways as more families have experience with Alzheimer’s disease.

scholarly journals PDE4D And HCN1 Ultrastructure In Rhesus Macaque Entorhinal Cortex: Relevance For Aging And Alzheimer's Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 638-639
Author(s):  
Dibyadeep Datta ◽  
SueAnn Mentone ◽  
Amy Arnsten
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Rhesus Macaque ◽  
Entorhinal Cortex ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Stellate Cell ◽  
Tau Pathology ◽  
Molecular Features

Abstract Tau pathology emerges in a distinct spatial and temporal pattern in Alzheimer’s Disease (AD). Anatomical studies in AD subjects and rhesus macaques show earliest signs of tau pathology in the stellate cell islands in entorhinal cortex (ERC) layer II. However, the molecular mechanisms that confer vulnerability to ERC layer II cells early in AD is unknown. cAMP-PKA magnification of calcium release has been seen in prefrontal cortex, associated with HCN channel opening to dynamically regulate synaptic strength. This process is regulated by phosphodiesterases (PDE), regulation that is lost with age. The current study examined whether this “signature of flexibility” could also be seen in layer II ERC, underlying vulnerability to tau pathology with aging. We used high-spatial resolution immunoEM to localize PDE4D and HCN1 in young rhesus macaque (7-10y) ERC layer II. Our results suggest that PDE4D was concentrated on the SER-spine apparatus and in postsynaptic density, and HCN1 expressed in the membrane near excitatory synapses in dendritic spines. Within dendritic shafts, PDE4D labeling was observed along microtubules and near mitochondria, whereas HCN1 was organized in discrete clusters along the plasma membrane. These data suggest that PDE4D is optimally positioned to modulate cAMP microdomains and control calcium extrusion from the SER. HCN1 channels are localized in subcompartments to facilitate dynamic physiological representation of sensory experience and visual space governed by cAMP-PKA signaling. The anatomical patterns in ERC layer II corroborate our findings in vulnerable glutamatergic circuits in prefrontal cortex, suggesting conserved molecular features in association cortices most susceptible in AD.

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

2020 ◽  
pp. 65-71
Author(s):  
Burbaeva G.Sh. ◽  
Androsova L.V. ◽  
Vorobyeva E.A. ◽  
Savushkina O.K.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Vascular Dementia ◽  
Binding Activity ◽  
Nephelometric Method ◽  
Rate Of Polymerization ◽  
Mental Diseases ◽  
And Control ◽  
The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

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