scholarly journals Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer’s Disease

2020 ◽  
Vol 77 (3) ◽  
pp. 1043-1056 ◽  
Author(s):  
Benjamin B. Tournier ◽  
Stergios Tsartsalis ◽  
Kelly Ceyzériat ◽  
Ben H. Fraser ◽  
Marie-Claude Grégoire ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Binding Sites ◽  
Temporal Cortex ◽  
Population Expansion ◽  
Cell Types ◽  
Translocator Protein ◽  
Cellular Origin

Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes.

scholarly journals In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1941 ◽  
Author(s):  
Benjamin B. Tournier ◽  
Stergios Tsartsalis ◽  
Kelly Ceyzériat ◽  
Valentina Garibotto ◽  
Philippe Millet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Time Course ◽  
Single Photon ◽  
Photon Emission ◽  
Cell Types ◽  
Translocator Protein ◽  
Emission Computed Tomography ◽  
Cellular Origin

In the last decade, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in in vivo imaging has attempted to demonstrate the presence of neuroinflammatory reactions by measuring the 18 kDa translocator protein (TSPO) expression in many diseases of the central nervous system. We focus on two pathological conditions for which neuropathological studies have shown the presence of neuroinflammation, which translates in opposite in vivo expression of TSPO. Alzheimer’s disease has been the most widely assessed with more than forty preclinical and clinical studies, showing overall that TSPO is upregulated in this condition, despite differences in the topography of this increase, its time-course and the associated cell types. In the case of schizophrenia, a reduction of TSPO has instead been observed, though the evidence remains scarce and contradictory. This review focuses on the key characteristics of TSPO as a biomarker of neuroinflammation in vivo, namely, on the cellular origin of the variations in its expression, on its possible biological/pathological role and on its variations across disease phases.

scholarly journals Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jonathan D. Cherry ◽  
Camille D. Esnault ◽  
Zachary H. Baucom ◽  
Yorghos Tripodis ◽  
Bertrand R. Huber ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Temporal Cortex ◽  
Head Impacts ◽  
Hippocampal Subfields ◽  
Mild Disease ◽  
Tau Isoforms ◽  
Ghost Tangles

AbstractChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

P3-250: The APOE-E4 allele is associated with greater atrophy of the temporal cortex in Alzheimer's disease: An in vivo MRI study

2008 ◽  
Vol 4 ◽  
pp. T594-T595 ◽  
Author(s):  
Michela Pievani ◽  
Cristina Testa ◽  
Francesca Sabattoli ◽  
Matteo Bonetti ◽  
Kiralee M. Hayashi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Cortex ◽  
E4 Allele ◽  
Mri Study

scholarly journals Investigating Markers of the NLRP3 Inflammasome Pathway in Alzheimer’s Disease: A Human Post-Mortem Study

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1753
Author(s):  
Hao Tang ◽  
Michael Harte
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Glial Cell ◽  
Nlrp3 Inflammasome ◽  
Cell Activation ◽  
Temporal Cortex ◽  
Activation Markers

Neuroinflammatory mechanisms with glial cell activation have been implicated in the pathogenic process of Alzheimer’s disease (AD). Activation of the NLRP3 inflammasome is an essential component of the neuroinflammatory response. A role for NLRP3 activation in AD is supported by both in vitro and in vivo preclinical studies with little direct investigation of AD brain tissue. RNA expression of genes of three glial cell markers, HLA-DRA, AIF-1 and GFAP; the components of the NLRP3 inflammasome NLRP3, ASC, and caspase-1; and downstream pre-inflammatory cytokines IL-1 β and IL-18, were investigated in the temporal cortex of AD patients and age- and sex-matched controls. Protein expression of GFAP was also assessed. Increases in both mRNA and protein expression were observed for GFAP in AD. There were no significant changes in other NLRP3 activation markers between groups. Our results indicate the involvement of astrocyte activation in AD, particularly in more severe patients. We found no evidence for the specific involvement of the NLRP3 inflammasome.

scholarly journals Association Between Visual Memory and In Vivo Amyloid and Tau Pathology in Preclinical Autosomal Dominant Alzheimer’s Disease

2020 ◽  
pp. 1-9
Author(s):  
Yamile Bocanegra ◽  
Joshua T. Fox-Fuller ◽  
Ana Baena ◽  
Edmarie Guzmán-Vélez ◽  
Clara Vila-Castelar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Verbal Memory ◽  
Visual Memory ◽  
Autosomal Dominant ◽  
Clinical Symptoms ◽  
Temporal Cortex ◽  
Inferior Temporal Cortex ◽  
Amyloid Burden

Abstract Objective: Visual memory (ViM) declines early in Alzheimer’s disease (AD). However, it is unclear whether ViM impairment is evident in the preclinical stage and relates to markers of AD pathology. We examined the relationship between ViM performance and in vivo markers of brain pathology in individuals with autosomal dominant AD (ADAD). Methods: Forty-five cognitively unimpaired individuals from a Colombian kindred with the Presenilin 1 (PSEN1) E280A ADAD mutation (19 carriers and 26 noncarriers) completed the Rey–Osterrieth Complex Figure immediate recall test, a measure of ViM. Cortical amyloid burden and regional tau deposition in the entorhinal cortex (EC) and inferior temporal cortex (IT) were measured using 11C-Pittsburgh compound B positron emission tomography (PET) and 11F-flortaucipir PET, respectively. Results: Cognitively unimpaired carriers and noncarriers did not differ on ViM performance. Compared to noncarriers, carriers had higher levels of cortical amyloid and regional tau in both the EC and IT. In cognitively unimpaired carriers, greater cortical amyloid burden, higher levels of regional tau, and greater age were associated with worse ViM performance. Only a moderate correlation between regional tau and ViM performance remained after adjusting for verbal memory scores. None of these correlations were observed in noncarriers. Conclusions: Results suggest that AD pathology and greater age are associated with worse ViM performance in ADAD before the onset of clinical symptoms. Further investigation with larger samples and longitudinal follow-up is needed to examine the utility of ViM measures for identifying individuals at high risk of developing dementia later in life.

scholarly journals Cerebrovascular and microglial states are not altered by functional neuroinflammatory gene variant

2016 ◽  
Vol 36 (4) ◽  
pp. 819-830 ◽  
Author(s):  
Daniel Felsky ◽  
Philip L De Jager ◽  
Julie A Schneider ◽  
Konstantinos Arfanakis ◽  
Debra A Fleischman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Protein A ◽  
Translocator Protein ◽  
Postmortem Brain ◽  
Amyloid Angiopathy ◽  
Religious Orders ◽  
Binding Characteristics

The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer’s disease, which is characterized by alterations in vascular and inflammatory states. A TSPO variant, rs6971, determines binding affinity of exogenous radioligands in vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer’s Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation. We found that rs6971 does not alter translocator protein in a way that impacts cerebrovascular and inflammatory states known to be affected in dementia.

Extreme Alleles at the Human Caveolin 1 Gene Novel Purine Complex and Risk of Alzheimer’s Disease

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
M. Ohadi ◽  
Y. Heshmati ◽  
A. Mirabzadeh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Binding Sites ◽  
Late Onset ◽  
Cell Types ◽  
Structural Protein ◽  
Aberrant Expression ◽  
Caveolin 1 ◽  
Wide Range

Caveolin-1 (CAV1) is the principal structural protein of caveolae membranes that are found in most cell types. Aberrant expression and mutation of this gene are associated with a wide range of disorders including neurodegenerative disorders and various cancers. We report a novel purine complex of three polymorphic motifs located at the enhancer region of the gene and risk of late-onset Alzheimer's disease. Extreme haplotypes with accumulated homozygosity for those haplotypes were observed in the Alzheimer's cases comparing with the controls (p< 0.000). Based on our findings, there is a window of haplotypes and haplotype lengths in the controls. Shorter and longer haplotypes were associated with Alzheimer's disease in our cases.This purine complex contains GGAA and GAAA motifs, the consensus binding sites for the Ets and IRF family transcription factors, respectively, and is highly conserved in distantly-related non-human primates in respect with location and motif sequence. The effect of the extreme haplotypes in the expression of the gene and the pathophysiology of Alzheimer's disease remain to be clarified.

P4-164: Mapping neuroinflammation in vivo in healthy aging and Alzheimer's disease: A PET study using a novel translocator protein 18kDA (TSPO) radioligand, [18F]-FEPPA

2012 ◽  
Vol 8 (4S_Part_19) ◽  
pp. P693-P693 ◽  
Author(s):  
Ivonne Suridjan ◽  
Rusjan Pablo ◽  
Bruce Pollock ◽  
Aristotle Voineskos ◽  
Alan Wilson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Translocator Protein

Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex

1991 ◽  
Vol 12 (3) ◽  
pp. 255-258 ◽  
Author(s):  
Diane Diorio ◽  
Sharon A. Welner ◽  
Roger F. Butterworth ◽  
Michael J. Meaney ◽  
Barbara E. Suranyi-Cadotte
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Sites ◽  
Temporal Cortex ◽  
Benzodiazepine Binding ◽  
Benzodiazepine Binding Sites

scholarly journals Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time

2020 ◽  
Author(s):  
Priya Prakash ◽  
Krupal P. Jethava ◽  
Nils Korte ◽  
Pablo Izquierdo ◽  
Emilia Favuzzi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Real Time ◽  
Glial Cells ◽  
Brain Slices ◽  
Amyloid Β ◽  
Disease Outcomes ◽  
Underlying Mechanisms ◽  
First Time

ABSTRACTPhagocytosis by glial cells is essential to regulate brain function during development and disease. Given recent interest in using amyloid β (Aβ)-targeted antibodies as a therapy for patients with Alzheimer’s disease, removal of Aβ by phagocytosis is likely protective early in Alzheimer’s disease, but remains poorly understood. Impaired phagocytic function of glial cells surrounding Aβ plaques during later stages in Alzheimer’s disease likely contributes to worsened disease outcomes, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ1-42 analogue (AβpH) that exhibits green fluorescence upon internalization into the acidic phagosomes of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of AβpH in real time in live animals. Microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. AβpH can be used to investigate the phagocytic mechanisms removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of Alzheimer’s disease.

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