Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia

Ghiso, Jorge; Frangione, Blas

doi:10.3233/jad-2001-3110

Cited by 58 publications

(35 citation statements)

References 56 publications

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“…Oxidative stress results in accumulation of potentially neurotoxic Aβ peptide by inducing the amyloidogenic process of AβPP and increasing the activity of β-secretase [82,83]. Cerebral amyloid angiopathy is associated with most cases of AD, characterized by Aβ deposits in brain vessels [84]. Oxidative stress is found triggering the amyloidogenic pathway in human vascular smooth muscle cells by up-regulation of AβPP cleaving enzyme 1 (BACE1) expression and secretion of Aβ1–40 and Aβ1–42 with mediation of c-Jun N -terminal Kinase and p38 MAPK [85].…”

Section: Ros Mediates Neurodegenerative Diseasesmentioning

confidence: 99%

Oxidative Stress and Neurodegenerative Disorders

Wuliji

et al. 2013

IJMS

374

246

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Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.

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Section: Ros Mediates Neurodegenerative Diseasesmentioning

confidence: 99%

Oxidative Stress and Neurodegenerative Disorders

Wuliji

et al. 2013

IJMS

374

246

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“…Alzheimer’s disease (AD), the most common form of amyloidosis and dementia in humans, is characterized by the deposition of amyloid-β (Aβ) in the brain parenchyma and cerebral vasculature as well as by the presence of hyperphosphorylated tau in intraneuronal neurofibrillary tangles [1, 2]. Although it is unclear what primarily triggers and drives the progression of AD, strong evidence supports a pathogenic role of Aβ oligomeric conformations [3–6].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration

Todd

Fossati

Ghiso

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Familial British dementia (FBD) is an early-onset non-amyloid-β (Aβ) cerebral amyloidosis that presents with severe cognitive decline and strikingly similar neuropathological features to those present in Alzheimer’s disease (AD). FBD is associated with a T to A single nucleotide transition in the stop codon of a gene encoding BRI2, leading to the production of an elongated precursor protein. Furin-like proteolytic processing at its C-terminus releases a longer-than-normal 34 amino acid peptide, ABri, exhibiting amyloidogenic properties not seen in its 23 amino acid physiologic counterpart Bri1-23. Deposited ABri exhibits abundant post-translational pyroglutamate (pE) formation at the N-terminus, a feature seen in truncated forms of Aβ found in AD deposits, and co-exists with neurofibrillary tangles almost identical to those found in AD. We tested the impact of the FBD mutation alone and in conjunction with the pE post-translational modification on the structural properties and associated neurotoxicity of the ABri peptide. The presence of pE conferred to the ABri molecule enhanced hydrophobicity and accelerated aggregation/fibrillization properties. ABri pE was capable of triggering oxidative stress, loss of mitochondrial membrane potential and activation of caspase-mediated apoptotic mechanisms in neuronal cells, whereas homologous peptides lacking the elongated C-terminus and/or the N-terminal pE were unable to induce similar detrimental cellular pathways. The data indicate that the presence of N-terminal pE is not in itself sufficient to induce pathogenic changes in the physiologic Bri1-23 peptide but that its combination with the ABri mutation is critical for the molecular pathogenesis of FBD.

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“…It likely affects processing of APP, leading to the formation of amyloid plaques in brain tissue and in walls of blood vessels serving the brain [33]. It is associated to stroke [34].…”

Section: Resultsmentioning

confidence: 99%

Protein Fragments: Functional and Structural Roles of Their Coevolution Networks

Dib

Carbone

2012

PLoS ONE

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Small protein fragments, and not just residues, can be used as basic building blocks to reconstruct networks of coevolved amino acids in proteins. Fragments often enter in physical contact one with the other and play a major biological role in the protein. The nature of these interactions might be multiple and spans beyond binding specificity, allosteric regulation and folding constraints. Indeed, coevolving fragments are indicators of important information explaining folding intermediates, peptide assembly, key mutations with known roles in genetic diseases, distinguished subfamily-dependent motifs and differentiated evolutionary pressures on protein regions. Coevolution analysis detects networks of fragments interaction and highlights a high order organization of fragments demonstrating the importance of studying at a deeper level this structure. We demonstrate that it can be applied to protein families that are highly conserved or represented by few sequences, enlarging in this manner, the class of proteins where coevolution analysis can be performed and making large-scale coevolution studies a feasible goal.

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Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia

Cited by 58 publications

References 56 publications

Oxidative Stress and Neurodegenerative Disorders

Oxidative Stress and Neurodegenerative Disorders

Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration

Protein Fragments: Functional and Structural Roles of Their Coevolution Networks

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