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 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.

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 Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

2019 ◽  
Vol 116 (36) ◽  
pp. 17963-17969 ◽  
Author(s):  
Katsuya Araki ◽  
Naoto Yagi ◽  
Koki Aoyama ◽  
Chi-Jing Choong ◽  
Hideki Hayakawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
X Ray Diffraction ◽  
Thin Sections ◽  
X Ray ◽  
Β Sheet ◽  
The Brain

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

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.

Modulation of ϐ-amyloid production and fibrillization

2001 ◽  
Vol 67 ◽  
pp. 1-14 ◽  
Author(s):  
David Allsop ◽  
Lance J. Twyman ◽  
Yvonne Davies ◽  
Susan Moore ◽  
Amber York ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Neurofibrillary Tangle ◽  
Neuronal Loss ◽  
Brain Parenchyma ◽  
Amino Acid Peptide ◽  
Close Relatives ◽  
The Brain

Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as ϐ-amyloid or Aϐ. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of Aϐ in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of Aϐ production and fibrillization.

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 Myopathy Associateci with Amyloid Angiopathy

1977 ◽  
Vol 4 (1) ◽  
pp. 77-80 ◽  
Author(s):  
Joseph Bruni ◽  
Juan M. Bilbao ◽  
Kenneth P. H. Pritzker
Keyword(s):  
Muscular Dystrophy ◽  
Peripheral Nerve ◽  
Blood Vessels ◽  
Clinical Picture ◽  
Inflammatory Myopathy ◽  
Plasma Cell Dyscrasia ◽  
Amyloid Angiopathy ◽  
Amyloid Deposits ◽  
Peripheral Nerve Involvement ◽  
Vessel Involvement

SummaryA 38-year-old patient with the clinical picture of a progressive myopathy resembling limb girdle muscular dystrophy is presented. Muscle biopsy showed amyloid deposits in the walls of small endomysial blood vessels. There was no clinical or physiological evidence of peripheral nerve involvement, no plasma cell dyscrasia and no generalized amyloidosis. There was no muscle fiber hypertrophy, inflammation or neurogenic change. There was no response to steroid therapy.The etiopathogenesis of this amyloid angiopathy is undetermined. The extensive vessel involvement with amyloid deposition and the absence of changes indicative of muscular dystrophy or inflammatory myopathy leads us to favor an ischemic basis for this patient’s myopathy.

scholarly journals The Neurovascular Unit Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2022 ◽  
Author(s):  
Luis O. Soto-Rojas ◽  
Mar Pacheco-Herrero ◽  
Paola A. Martínez-Gómez ◽  
B. Berenice Campa-Córdoba ◽  
Ricardo Apátiga-Pérez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Vascular Risk ◽  
Therapeutic Approaches ◽  
The Brain

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

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