scholarly journals Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer’s Disease Brains

2021 ◽  
pp. 1-11
Author(s):  
Suman Chaudhary ◽  
Ajay Ashok ◽  
Dallas McDonald ◽  
Aaron S. Wise ◽  
Alexander E. Kritikos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Stage I ◽  
Iron Accumulation ◽  
Stage Iii ◽  
Braak Stage ◽  
Tissue Iron ◽  
Consistent Feature ◽  
Total Tissue

Background: Accumulation of iron is a consistent feature of Alzheimer’s disease (AD) brains. The underlying cause, however, remains debatable. Objective: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. Methods: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ2 was determined by western blotting. Total tissue iron was determined by colorimetry. Results: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. Conclusion: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron.

The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease

2018 ◽  
Vol 15 (5) ◽  
pp. 462-473 ◽  
Author(s):  
Wen-Ying Qiu ◽  
Qian Yang ◽  
Wanying Zhang ◽  
Naili Wang ◽  
Di Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Postmortem Brain ◽  
Braak Stage ◽  
Brain Bank ◽  
General Linear Multivariate Model ◽  
Human Brains

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

PET/MRI Delivers Multimodal Brain Signature in Alzheimer’s Disease with De Novo PSEN1 Mutation

2021 ◽  
Vol 18 ◽  
Author(s):  
Gayane Aghakhanyan ◽  
Dorothee Saur ◽  
Michael Rullmann ◽  
Christopher M. Weise ◽  
Matthias L. Schroeter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Diffusion Tensor ◽  
Molecular Genetic ◽  
Pathogenic Variant ◽  
Stage Iii ◽  
Braak Stage ◽  
Subcortical Structures ◽  
Functional Brain

Background: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer’s disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap. Material and Methods: We presented a 31-year-old male patient without a family history of de- mentia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [18F]Florbetaben and the second-- generation tau tracer [18F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls. Results: Widespread β-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disrup- tion of default mode and sensory-motor network functional connectivity. Molecular genetic analy- sis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val). Conclusion: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an ar- ray of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating an- ti-amyloid/tau therapeutic approaches.

scholarly journals Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yu Guo ◽  
◽  
Yu-Yuan Huang ◽  
Xue-Ning Shen ◽  
Shi-Dong Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Regions Of Interest ◽  
Emission Tomography ◽  
Braak Stage ◽  
Positron Emission ◽  
Tau Pet

Abstract Background We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET). Methods In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared. Results Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology. Conclusions Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

scholarly journals Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Nicholas J. Ashton ◽  
Tharick A. Pascoal ◽  
Thomas K. Karikari ◽  
Andréa L. Benedet ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Great Promise ◽  
Braak Stage ◽  
Braak Staging ◽  
Positron Emission

AbstractThe quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

Neuroinflammation and Complexes of 17β -Hydroxysteroid Dehydrogenase type 10 - Amyloid β in Alzheimer's Disease

2013 ◽  
Vol 10 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Zdena Kristofikova ◽  
Daniela Ripova ◽  
Ales Bartos ◽  
Marketa Bockova ◽  
Katerina Hegnerova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Hydroxysteroid Dehydrogenase

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

Sign in / Sign up

Export Citation Format

Share Document