scholarly journals The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer’s Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis

2020 ◽  
Vol 10 (8) ◽  
pp. 503
Author(s):  
Andrew King ◽  
Boglarka Szekely ◽  
Eda Calapkulu ◽  
Hanan Ali ◽  
Francesca Rios ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
White Matter ◽  
Cell Density ◽  
Animal Studies ◽  
Post Mortem ◽  
Disease Pathogenesis ◽  
And Control ◽  
The Relationship

There is increasing evidence of astrocyte dysfunction in the pathogenesis of Alzheimer’s disease (AD). Animal studies supported by human post-mortem work have demonstrated two main astrocyte types: the C3 immunopositive neurotoxic A1 astrocytes and the S100A10 immunopositive neuroprotective A2 astrocytes. A1 astrocytes predominate in AD, but the number of cases has been relatively small. We examined post-mortem brains from a larger cohort of AD cases and controls employing C3 and S100 immunohistochemistry to identify the astrocytic subtypes. There were a number of C3 immunopositive astrocyte-like cells (ASLCs) in the control cases, especially in the lower cerebral cortex and white matter. In AD this cell density appeared to be increased in the upper cerebral cortex but was similar to controls in other regions. The S100A10 showed minimal immunopositivity in the control cases in the cortex and white matter, but there was increased ASLC density in upper/lower cortex and white matter in AD compared to controls. In AD and control cases the numbers of C3 immunopositive ASLCs were greater than those for S100A10 ASLCs in all areas studied. It would appear that the relationship between A1 and A2 astrocytes and their possible role in the pathogenesis of AD is complex and requires more research.

scholarly journals Small RNA modifications in Alzheimer’s disease

2020 ◽  
Author(s):  
Xudong Zhang ◽  
Fatima Trebak ◽  
Lucas AC Souza ◽  
Junchao Shi ◽  
Tong Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Prefrontal Cortex ◽  
Small Rna ◽  
Small Rnas ◽  
Post Mortem ◽  
Rna Modifications ◽  
Non Coding Rnas ◽  
And Control

AbstractBackgroundWhile significant advances have been made in uncovering the aetiology of Alzheimer’s disease and related dementias at the genetic level, molecular events at the epigenetic level remain largely undefined. Emerging evidence indicates that small non-coding RNAs (sncRNAs) and their associated RNA modifications are important regulators of complex physiological and pathological processes, including aging, stress responses, and epigenetic inheritance. However, whether small RNAs and their modifications are altered in dementia is not known.MethodsWe performed LC-MS/MS–based, high-throughput assays of small RNA modifications in post-mortem samples of the prefrontal lobe cortices of Alzheimer’s disease (AD) and control individuals. We noted that some of the AD patients has co-occurring vascular cognitive impairment-related pathology (VaD).FindingsWe report altered small RNA modifications in AD samples compared with normal controls. The 15–25-nucleotide (nt) RNA fraction of these samples was enriched for microRNAs, whereas the 30–40-nt RNA fraction was enriched for tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). Interestingly, most of these altered RNA modifications were detected both in the AD and AD with co-occurring vascular dementia subjects. In addition, sequencing of small RNA in the 30–40-nt fraction from AD cortices revealed reductions in rsRNA-5S, tsRNA-Tyr, and tsRNA-Arg.InterpretationThese data suggest that sncRNAs and their associated modifications are novel signals that may be linked to the pathogenesis and development of Alzheimer’s disease.FundingNIH grants (R01HL122770, R01HL091905, 1P20GM130459, R01HD092431, P50HD098593, GM103440), AHA grant (17IRG33370128), Sigmund Gestetner Foundation Fellowship to P Kehoe.Research in ContextEvidence before this studyAlzheimer’s disease (AD) and vascular dementia (VaD) are marked by cognitive impairment and neuropathologies caused by significant neuronal death. Associated gene mutations are rare in subjects with dementia, and the aetiology of these diseases is still not completely understood. Recent emerging evidence suggests that epigenetic changes are risk factors for the development of dementia. However, studies assessing small RNA modifications—one of the features of epigenetics—in dementia are lacking.Added value of this studyWe used high-throughput liquid chromatography-tandem mass spectrometry and small RNA sequencing to profile small RNA modifications and the composition of small RNAs in post-mortem samples of the prefrontal cortex of AD and control subjects. We detected and quantified 16 types of RNA modifications and identified distinct small non-coding RNAs and modification signatures in AD subjects compared with controls.Implications of all the available evidenceThis study identified novel types and compositions of small RNA modifications in the prefrontal cortex of AD patients compared with control subjects in post-mortem samples. The cellular locations of these RNA modifications and whether they are drivers or outcomes of AD are still not known. However, results from the present study may open new possibilities for dissecting the dementia pathology.

scholarly journals Platelet phosphorylated TDP-43: An exploratory study for a peripheral surrogate biomarker development for Alzheimer’s disease

2017 ◽  
Author(s):  
Rodger Wilhite ◽  
Jessica Sage ◽  
Abdurrahman Bouzid ◽  
Tyler Primavera ◽  
Abdulbaki Agbas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Clinical Signs ◽  
Brain Regions ◽  
Post Mortem ◽  
Disease Prognosis ◽  
Post Mortem Brain ◽  
And Control ◽  
Lateral Sclerosis

AbstractAim: Alzheimer’s disease (AD) and other forms of dementia create a non-curable disease population in World’s societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & Methods: TDP-43 levels were analyzed in post-mortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in post-mortem AD brain regions and similar trends were also observed in patient’s platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible, and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis.Lay abstractIn this study, we explore to identify an Alzheimer’s disease-selective phospho-specific antibody that recognizes the diseased form of TDP-43 protein in patient’s blood-derived platelets. Our results suggest that selective anti-phosphorylated TDP-43 antibody discriminates Alzheimer’s disease from non-demented controls and patients with amyotrophic lateral sclerosis. Therefore, platelet screening with a selective antibody could potentially be a useful tool for diagnostic purposes for Alzheimer’s disease.

scholarly journals Tumor necrosis factor-alpha - potential target for neuroprotector dimebon

2016 ◽  
Vol 62 (4) ◽  
pp. 418-425 ◽  
Author(s):  
A.V. Alessenko ◽  
S.O. Bachurin ◽  
S.V. Gurianova ◽  
Y.O. Karatasso ◽  
E.F. Shevtsova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Molecular Species ◽  
Animal Studies ◽  
Neuroprotective Effect ◽  
New Drugs ◽  
Necrosis Factor Alpha ◽  
Positive Effects ◽  
New Therapeutic Approaches

Dimebon (Dimebolin) is an antihistamine drug which has been used in Russia since 1983. Recently Dimebolin has attracted renewed interest after being shown to have positive effects on persons suffering from Alzheimer's disease. Animal studies have shown that dimebon acts through multiple mechanisms, both blocking the action of neurotoxic beta-amyloid peptides and inhibiting L-type calcium channels, modulating the action of AMPA and NMDA glutamate receptors. Our experiments with cell culture L929 and mice have shown that dimebon may exert its neuroprotective effect by blocking cytotoxic signals induced by proinflammatory cytokines such as TNF-a which are believed to play a central role in Alzheimer's disease. Dimebon (10 mg/ml) protected mouse fibroblasts L929 against the toxic action of TNF-a. Our study included 65 male mice. TNF-a (10 mg per mouse), dimebon (0,2 mg/kg) and their combination were injected intraperitonealy. Changes in the level of molecular species of sphingomyelin and galactosyl ceramide in hippocampus, cerebellum and cerebral cortex within 30 min, 2 h, 4 h, and 24 h after injection were detected by chromato-mass-spectrometry. Maximal changes in sphingomyelin and galactosyl ceramides contents of different molecular species after single TNF-a administration were found in the hippocampus, and were less expressed in the cerebral cortex and cerebellum after 24 h. Dimebon itself did not induce changes in the sphingolipid spectrum in brain sections, but protected them against disorders induced by TNF-a in the brain. Modern strategies in the search of new therapeutic approaches are based on the multitarget properties of new drugs. According to our results TNF-a may serve as a new target for dimebon.

[P1-116]: THE RELATIONSHIP BETWEEN AMYLOID IN THE RETINA AND A BRAIN-BASED POST-MORTEM DIAGNOSIS OF ALZHEIMER's DISEASE

2017 ◽  
Vol 13 (7S_Part_5) ◽  
pp. P284-P285 ◽  
Author(s):  
Melanie C.W. Campbell ◽  
Frank Corapi ◽  
Laura Emptage ◽  
Rachel Redekop ◽  
Namrata Shah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Post Mortem ◽  
The Relationship

scholarly journals Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Marie-Victoire Guillot-Sestier ◽  
Ana Rubio Araiz ◽  
Virginia Mela ◽  
Aline Sayd Gaban ◽  
Eoin O’Neill ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sexual Dimorphism ◽  
Microglial Activation ◽  
Post Mortem ◽  
Disease Pathogenesis ◽  
Plaque Load ◽  
Males And Females ◽  
Age And Sex

AbstractAge and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.

scholarly journals Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

2009 ◽  
Vol 22 (1_suppl) ◽  
pp. 51-63
Author(s):  
A. A. Gouw ◽  
A. Seewann ◽  
H. Vrenken ◽  
W. M. van der Flier ◽  
J. M. Rozemuller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Microglial Activation ◽  
White Matter Hyperintensities ◽  
Quantitative Mri ◽  
Post Mortem ◽  
Patient Groups ◽  
The Difference ◽  
Axonal Density

White matter hyperintensities (WMH) are frequently seen on T2-weighted MRI scans of elderly subjects with and without Alzheimer's disease. WMH are only weakly and inconsistently associated with cognitive decline, which may be explained by heterogeneity of the underlying neuropathological substrates. The use of quantitative MRI could increase specificity for these neuropathological changes. We assessed whether post-mortem quantitative MRI is able to reflect differences in neuropathological correlates of WMH in tissue samples obtained post-mortem from Alzheimer's disease patients and from non-demented elderly. Thirty-three formalin-fixed, coronal brain slices from II Alzheimer's disease patients (mean age: 83 ± 10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 ± 10 years, four females) with WMH were scanned at 1.5 T using qualitative (fluid-attenuated inversion recovery, FLAIR) and quantitative MRI [diffusion tensor imaging (DTI) including estimation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and T1-relaxation time mapping based on flip-angle array). A total of 104 regions of interest were defined on FLAIR images in WMH and normal appearing white matter (NAWM). Neuropathological examination included (semiquantitative assessment of axonal density (Bodian), myelin density (LFB), astrogliosis (GFAP) and microglial activation (HLA-DR). Patient groups (Alzheimer's disease versus controls) and tissue types (WMH versus NAWM) were compared with respect to QMRI and neuropathological measures. Overall, Alzheimer's disease patients had significantly lower FA ( P < 0.01) and higher T1-values than controls ( P = 0.04). WMH showed lower FA ( P < 0.01) and higher T1-values ( P < 0.001) than NAWM in both patient groups. A significant interaction between patient group and tissue type was found for the T1 measurements, indicating that the difference in T1-relaxation time between NAWM and WMH was larger in Alzheimer's disease patients than in non-demented controls. All neuropathological measures showed differences between WMH and NAWM, although the difference in microglial activation was specific for Alzheimer's disease. Multivariate regression models revealed that in Alzheimer's disease, axonal density was an independent determinant of FA, whereas T1 was independently determined by axonal and myelin density and microglial activation. Quantitative MRI techniques reveal differences in WMH between Alzheimer's disease and non-demented elderly, and are able to reflect the severity of the neuropathological changes involved.

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