scholarly journals Exogenous Aβ seeds induce Aβ depositions in the blood vessels rather than the brain parenchyma, independently of Aβ strain-specific information

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tsuyoshi Hamaguchi ◽  
Jee Hee Kim ◽  
Akane Hasegawa ◽  
Ritsuko Goto ◽  
Kenji Sakai ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Vessels ◽  
Brain Homogenate ◽  
Brain Parenchyma ◽  
Brain Extract ◽  
Amyloid Angiopathy ◽  
Specific Information ◽  
Brain Extracts ◽  
Iatrogenic Transmission ◽  
The Brain

AbstractLittle is known about the effects of parenchymal or vascular amyloid β peptide (Aβ) deposition in the brain. We hypothesized that Aβ strain-specific information defines whether Aβ deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aβ plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer’s disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aβ. One year after the injection, the pathological and biochemical features of Aβ in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aβ depositions were observed in the mice that were injected with the human brain homogenate from the less Aβ group. The Aβ and CAA seeding activities, which had significant positive correlations with the Aβ oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aβ group than in the other three groups. These results indicate that exogenous Aβ seeds from different Aβ pathologies induced Aβ deposition in the blood vessels rather than the brain parenchyma without being influenced by Aβ strain-specific information, which might be why CAA is a predominant feature of Aβ pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aβ pathology might occur due to contamination of brain tissues from patients with little Aβ pathology, and the development of inactivation methods for Aβ seeding activity to prevent iatrogenic transmission is urgently required.

scholarly journals Copper stabilizes antiparallel β-sheet fibrils of the amyloid β40 (Aβ40)-Iowa variant

2020 ◽  
Vol 295 (27) ◽  
pp. 8914-8927
Author(s):  
Elliot J. Crooks ◽  
Brandon A. Irizarry ◽  
Martine Ziliox ◽  
Toru Kawakami ◽  
Tiffany Victor ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Amyloid Fibrils ◽  
Brain Parenchyma ◽  
Amyloid Peptide ◽  
Amyloid Angiopathy ◽  
Seeded Growth ◽  
Amyloid Deposits ◽  
Aβ42 Peptide ◽  
Β Sheet ◽  
The Brain

Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue–long β-amyloid peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.

scholarly journals The brain timewise: how timing shapes and supports brain function

2015 ◽  
Vol 370 (1668) ◽  
pp. 20140170 ◽  
Author(s):  
Riitta Hari ◽  
Lauri Parkkonen
Keyword(s):  
Human Brain ◽  
Brain Imaging ◽  
Brain Function ◽  
Temporal Dynamics ◽  
Generative Models ◽  
Network Activity ◽  
Brain Diseases ◽  
Specific Information ◽  
Non Invasive ◽  
The Brain

We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the dynamics of the human brain with non-invasive measurements. Accurate timing is important for the interplay of neurons, neuronal circuitries, brain areas and human individuals. In the human brain, multiple temporal integration windows are hierarchically organized, with temporal scales ranging from microseconds to tens and hundreds of milliseconds for perceptual, motor and cognitive functions, and up to minutes, hours and even months for hormonal and mood changes. Accurate timing is impaired in several brain diseases. From the current repertoire of non-invasive brain imaging methods, only magnetoencephalography (MEG) and scalp electroencephalography (EEG) provide millisecond time-resolution; our focus in this paper is on MEG. Since the introduction of high-density whole-scalp MEG/EEG coverage in the 1990s, the instrumentation has not changed drastically; yet, novel data analyses are advancing the field rapidly by shifting the focus from the mere pinpointing of activity hotspots to seeking stimulus- or task-specific information and to characterizing functional networks. During the next decades, we can expect increased spatial resolution and accuracy of the time-resolved brain imaging and better understanding of brain function, especially its temporal constraints, with the development of novel instrumentation and finer-grained, physiologically inspired generative models of local and network activity. Merging both spatial and temporal information with increasing accuracy and carrying out recordings in naturalistic conditions, including social interaction, will bring much new information about human brain function.

Antibodies to β-Amyloid Decrease the Blood-to-Brain Transfer of β-Amyloid Peptide1

2002 ◽  
Vol 227 (8) ◽  
pp. 609-615 ◽  
Author(s):  
Weihong Pan ◽  
Beka Solomon ◽  
Lawrence M. Maness ◽  
Abba J. Kastin
Keyword(s):  
Ex Vivo ◽  
Amyloid Β ◽  
Brain Perfusion ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Β Amyloid ◽  
Blocking Antibodies ◽  
The Brain

Amyloid-β peptides (Aβ) play an important role in the pathophysiology of dementia of the Alzheimer's type and in amyloid angiopathy. Aβ outside the CNS could contribute to plaque formation in the brain where its entry would involve interactions with the blood-brain barrier (BBB). Effective antibodies to Aβ have been developed in an effort to vaccinate against Alzheimer's disease. These antibodies could interact with Aβ in the peripheral blood, block the passage of Aβ across the BBB, or prevent Aβ deposition within the CNS. To determine whether the blocking antibodies act at the BBB level, we examined the influx of radiolabeled Aβ (125I-Aβ1-40) into the brain after ex-vivo incubation with the antibodies. Antibody mAb3D6 (élan Company) reduced the blood-to-brain influx of Aβ after iv bolus injection. It also significantly decreased the accumulation of Aβ in brain parenchyma. To confirm the in-vivo study and examine the specificity of mAb3D6, in-situ brain perfusion in serum-free buffer was performed after incubation of 125I-Aβ1-40 with another antibody mAbmc1 (DAKO Company). The presence of mAbmc1 also caused significant reduction of the influx of Aβ into the brain after perfusion. Therefore, effective antibodies to Aβ can reduce the influx of Aβ1-40 into the brain.

scholarly journals The Expression of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) in Hippocampal Arterioles Declines During Progression of Alzheimer’s Disease

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Kelley E Anderson ◽  
Thomas A Bellio ◽  
Emily Aniskovich ◽  
Stephanie L Adams ◽  
Jan Krzysztof Blusztajn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Vessels ◽  
Pyramidal Neurons ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Type I ◽  
Clinical Dementia Rating ◽  
Activin Receptor ◽  
Receptor Like Kinase

Abstract Cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD)—deposition of beta amyloid (Aβ) within the walls of cerebral blood vessels—typically accompanies Aβ buildup in brain parenchyma and causes abnormalities in vessel structure and function. We recently demonstrated that the immunoreactivity of activin receptor-like kinase 1 (ALK1), the type I receptor for circulating BMP9/BMP10 (bone morphogenetic protein) signaling proteins, is reduced in advanced, but not early stages of AD in CA3 pyramidal neurons. Here we characterize vascular expression of ALK1 in the context of progressive AD pathology accompanied by amyloid angiopathy in postmortem hippocampi using immunohistochemical methods. Hippocampal arteriolar wall ALK1 signal intensity was 35% lower in AD patients (Braak and Braak Stages IV and V [BBIV-V]; clinical dementia rating [CDR1-2]) as compared with subjects with early AD pathologic changes but either cognitively intact or with minimal cognitive impairment (BBIII; CDR0-0.5). The intensity of Aβ signal in arteriolar walls was similar in all analyzed cases. These data suggest that, as demonstrated previously for specific neuronal populations, ALK1 expression in blood vessels is also vulnerable to the AD pathophysiologic process, perhaps related to CAA. However, cortical arterioles may remain responsive to the ALK1 ligands, such as BMP9 and BMP10 in early and moderate AD.

scholarly journals Characterisation of the invasive tumour niche using astrocyte-glioblastoma organoids and decellularised human brain

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv7-iv7
Author(s):  
Mohammed Diksin ◽  
Jonathan Rowlinson ◽  
Alexandar Kondrashov ◽  
Chris Denning ◽  
Jamie Hughes ◽  
...  
Keyword(s):  
Human Brain ◽  
Cross Talk ◽  
Secondary Ion Mass Spectrometry ◽  
Brain Parenchyma ◽  
Brain Extract ◽  
Malignant Cells ◽  
3D Scaffold ◽  
Glioma Invasion ◽  
Naive Patient ◽  
Invasive Margin

Abstract Glioblastoma therapeutic challenges are in considerable part due to myriad survival adaptations and mechanisms, which allow malignant cells to repurpose signalling pathways within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from repressive factors that represent anti-cancer defence mechanisms. We hypothesised that pre-clinical modelling of glioma invasion by recapitulating early events occurring immediately after surgery at the glioblastoma invasive margin, could reveal the cross-talk between malignant cells and the surrounding healthy astrocytes, which facilitates tumour recurrence. We first generated transgenic H1-derived neural stem cells using CRISPR/Cas9-mediated knock-in of the YFP reporter gene under the control of the GFAP promoter. Reproducible ultrahigh-throughput AggreWells™ (19,200 micro-wells per 24-well plate) were used to create astrocyte-glioblastoma organoids, which we term ‘Gliomasphere Matrices’. YFP-labelled astrocytes were co-cultured with 10 treatment-naïve patient-derived cell lines isolated from the 5-aminolevulinic (5ALA)-determined glioblastoma invasive margin. Co-cultures were seeded upon on a sequentially constructed, time-of-flight secondary ion mass spectrometry (ToF-SIMS)-characterised 3D scaffold, composed of decellularised human brain extract with defined PEGDA hydrogel. YFP-astrocytes were purified from each of the 10 Gliomasphere Matrices using fluorescence-activated cell sorting (FACS) after 6- and 10-days co-culture. RNAseq profiling to address both putative astrocytic reprogramming by invasive glioblastoma cells and gene expression changes intrinsic to tumour cells will be discussed in relation to RNAseq data from patient-derived 5ALA FACS-purified glioblastoma invasive margin tissue. This novel multi-faceted model offers a unique opportunity to recapitulate early molecular cross-talk which facilitates glioblastoma recurrence and may be utilised for high-throughput drug screening.

scholarly journals Endothelial expression of human APP leads to cerebral amyloid angiopathy in mice

2020 ◽  
Author(s):  
Yuriko Tachida ◽  
Saori Miura ◽  
Rie Imamaki ◽  
Naomi Ogasawara ◽  
Hiroyuki Takuwa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Angiopathy ◽  
Disease Mechanisms ◽  
Age Dependent ◽  
Cerebral Amyloid ◽  
The Brain

AbstractThe deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in more than 90% of Alzheimer’s disease (AD) patients. The presence of such CAA pathology is not as evident, however, in most mouse models of AD, thereby making it difficult to examine the contribution of CAA to the pathogenesis of AD. Since blood levels of soluble amyloid precursor protein (sAPP) in rodents are less than 1% of those in humans, we hypothesized that endothelial APP expression would be markedly lower in rodents, thus providing a reason for the poorly expressed CAA pathology. Here we generated mice that specifically express human APP770 in endothelial cells. These mice exhibited an age-dependent robust deposition of Aβ in brain blood vessels but not in the parenchyma. Crossing these animals with APP knock-in mice led to an expanded CAA pathology as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results show that both neuronal and endothelial APP contribute cooperatively to vascular Aβ deposition, and suggest that this mouse model will be useful for studying disease mechanisms underlying CAA and for developing novel AD therapeutics.

scholarly journals Distribution and Cellular Localization of Prostacyclin Synthase in Human Brain

2000 ◽  
Vol 48 (5) ◽  
pp. 631-641 ◽  
Author(s):  
Isabel Siegle ◽  
Thomas Klein ◽  
Ming-Hui Zou ◽  
Peter Fritz ◽  
Martin Kömhoff
Keyword(s):  
Human Brain ◽  
Blood Vessels ◽  
Cellular Localization ◽  
Regional Distribution ◽  
Pyramidal Cells ◽  
Brain Homogenate ◽  
The Central Nervous System ◽  
Prostacyclin Synthase

SUMMARY Prostacyclin (PGI2) is a labile, lipid-derived metabolite of arachidonic acid synthesized through the sequential action of cyclo-oxygenase (COX) and prostacyclin synthase (PGIS). In addition to its well-characterized vasodilatory and thrombolytic effects, an increasing number of studies report an important role of PGI2 in nociception in various animal species. In this study we investigated the regional distribution of PGIS in human brain by immunohistochemistry and in situ hybridization. PGIS-immunoreactive (ir) protein was localized to blood vessels throughout the brain. Neuronal cells and glial cells, such as microglia and oligodendrocytes, also showed intense labeling. The strongest expression of PGIS was seen in large principal neurons, such as pyramidal cells of the cortex, pyramidal cells of the hippocampus, and Purkinje cells of the cerebellum. Abundance of PGIS mRNA was observed in blood vessels and large neurons and correlated well with the immunohistochemical findings. The expression of PGIS in human brain was further demonstrated by immunoblotting and detection of 6-keto-PGF1α, the stable degradation product of prostacyclin in human brain homogenate. These results demonstrate a widespread expression of PGIS in the central nervous system and suggest a potentially important role of prostacylin in modulating neuronal activity in human brain.

99mTc-labeled benzothiazole and stilbene derivatives as imaging agents for Aβ plaques in cerebral amyloid angiopathy

MedChemComm ◽  
2014 ◽  
Vol 5 (2) ◽  
pp. 153-158 ◽  
Author(s):  
Jianhua Jia ◽  
Mengchao Cui ◽  
Jiapei Dai ◽  
Xuedan Wang ◽  
Yu-Shin Ding ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Spect Imaging ◽  
Imaging Agents ◽  
Amyloid Angiopathy ◽  
Stilbene Derivatives ◽  
Cerebral Amyloid ◽  
The Brain

99mTc-labeled probes in this study for the Aβ plaques in the blood vessels of the brain may be used as SPECT imaging agents for the diagnosis of CAA.

scholarly journals Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways

2017 ◽  
Vol 114 (33) ◽  
pp. E6962-E6971 ◽  
Author(s):  
Aleksandra M. Wojtas ◽  
Silvia S. Kang ◽  
Benjamin M. Olley ◽  
Maureen Gatherer ◽  
Mitsuru Shinohara ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Fold Increase ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Clinical Complications ◽  
Perivascular Drainage

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood–brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu+/+ or Clu−/− background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu−/− mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu−/− mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

scholarly journals Synapsin I: an actin-bundling protein under phosphorylation control.

1987 ◽  
Vol 105 (3) ◽  
pp. 1355-1363 ◽  
Author(s):  
T C Petrucci ◽  
J S Morrow
Keyword(s):  
Actin Filaments ◽  
Binding Activity ◽  
Brain Extract ◽  
Synapsin I ◽  
Peptide Fragments ◽  
Molecular Weights ◽  
Brain Extracts ◽  
The Brain ◽  
Precise Role

Synapsin I is a neuronal phosphoprotein comprised of two closely related polypeptides with apparent molecular weights of 78,000 and 76,000. It is found in association with the small vesicles clustered at the presynaptic junction. Its precise role is unknown, although it probably participates in vesicle clustering and/or release. Synapsin I is known to associate with vesicle membranes, microtubules, and neurofilaments. We have examined the interaction of purified phosphorylated and unphosphorylated bovine and human synapsin I with tubulin and actin filaments, using cosedimentation, viscometric, electrophoretic, and morphologic assays. As purified from brain homogenates, synapsin I decreases the steady-state viscosity of solutions containing F-actin, enhances the sedimentation of actin, and bundles actin filaments. Phosphorylation by cAMP-dependent kinase has minimal effect on this interaction, while phosphorylation by brain extracts or by purified calcium- and calmodulin-dependent kinase II reduces its actin-bundling and -binding activity. Synapsin's microtubule-binding activity, conversely, is stimulated after phosphorylation by the brain extract. Two complementary peptide fragments of synapsin generated by 2-nitro-5-thiocyanobenzoic cleavage and which map to opposite ends of the molecule participate in the bundling process, either by binding directly to actin or by binding to other synapsin I molecules. 2-Nitro-5-thiocyanobenzoic peptides arising from the central portion of the molecule demonstrate neither activity. In vivo, synapsin I may link small synaptic vesicles to the actin-based cortical cytoskeleton, and coordinate their availability for release in a Ca++-dependent fashion.

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