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Amyloidosis Associated with Cerebral Amyloid Angiopathy: Cell Signaling Pathways Elicited in Cerebral Endothelial Cells

Ghiso, Jorge; Fossati, Silvia; Rostagno, Agueda
Substantial genetic, biochemical, and in vivo data indicate that progressive accumulation of amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Historically centered in the importance of parenchymal plaques, the role of cerebral amyloid angiopathy (CAA)-a frequently neglected amyloid deposit present in >80% of AD cases-for the mechanism of disease pathogenesis is now starting to emerge. CAA consistently associates with microvascular modifications, ischemic lesions, micro- and macro-hemorrhages, and dementia, progressively affecting cerebral blood flow, altering blood-brain barrier permeability, interfering with brain clearance mechanisms and triggering a cascade of deleterious pro-inflammatory and metabolic events that compromise the integrity of the neurovascular unit. New evidence highlights the contribution of pre-fibrillar Abeta in the induction of cerebral endothelial cell dysfunction. The recently discovered interaction of oligomeric Abeta species with TRAIL DR4 and DR5 cell surface death receptors mediates the engagement of mitochondrial pathways and sequential activation of multiple caspases, eliciting a cascade of cell death mechanisms while unveiling an opportunity for exploring mechanistic-based therapeutic interventions to preserve the integrity of the neurovascular unit.
PMID: 24670400
ISSN: 1387-2877
CID: 871452

Cytokines and disease

Orzechowski, Arkadiusz; Rostagno, Agueda A; Pucci, Sabina; Chiocchia, Gilles
PMID: 25301979
ISSN: 0962-9351
CID: 1310902

Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid beta and the Asn23 Iowa mutation

Fossati, Silvia; Todd, Krysti; Sotolongo, Krystal; Ghiso, Jorge; Rostagno, Agueda
Mutations within the Abeta (amyloid beta) peptide, especially those clustered at residues 21-23, are linked to early-onset AD (Alzheimer's disease) and primarily associated with cerebral amyloid angiopathy. The Iowa variant, a substitution of an aspartic acid residue for asparagine at position 23 (D23N), associates with widespread vascular amyloid and abundant diffuse pre-amyloid lesions significantly exceeding the incidence of mature plaques. Brain Iowa deposits consist primarily of a mixture of mutated and non-mutated Abeta species exhibiting partial aspartate isomerization at positions 1, 7 and 23. The present study analysed the contribution of the post-translational modification and the D23N mutation to the aggregation/fibrillization and cell toxicity properties of Abeta providing insight into the elicited cell death mechanisms. The induction of apoptosis by the different Abeta species correlated with their oligomerization/fibrillization propensity and beta-sheet content. Although cell toxicity was primarily driven by the D23N mutation, all Abeta isoforms tested were capable, albeit at different time frames, of eliciting comparable apoptotic pathways with mitochondrial engagement and cytochrome c release to the cytoplasm in both neuronal and microvascular endothelial cells. Methazolamide, a cytochrome c release inhibitor, exerted a protective effect in both cell types, suggesting that pharmacological targeting of mitochondria may constitute a viable therapeutic avenue.
PMID: 24028142
ISSN: 0264-6021
CID: 652202

Low Cerebrospinal Fluid Pressure in the Pathogenesis of Primary Open-Angle Glaucoma: Epiphenomenon or Causal Relationship? The Beijing Intracranial and Intraocular Pressure (iCOP) Study (vol 22, pg S11, 2013) [Correction]

Ghiso, Jorge A. ; Doudevski, Ivo ; Ritch, Robert ; Rostagno, Agueda A.
ISSN: 1057-0829
CID: 656682

Alzheimer's disease and glaucoma: mechanistic similarities and differences

Ghiso, Jorge A; Doudevski, Ivo; Ritch, Robert; Rostagno, Agueda A
Alzheimer's disease (AD) is the most common form of dementia. Intraneuronal neurofibrillary tangles, extracellular Abeta amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy, and synaptic and neuronal loss co-exist in the brain parenchyma, with the limbic areas being the most severely affected. The classic clinical findings are personality changes, progressive cognitive dysfunction, and loss of ability to perform activities of daily living. Visual impairment is common and appears related to disease severity, suggesting that visual testing may provide a method of screening and tracking AD changes. Although still not fully understood, research and clinical findings point to a possible common causal relationship between AD and glaucoma. These two chronic neurodegenerative disorders share biological and mechanistic features, among them (1) a strong age-related incidence, (2) retinal ganglion cell degeneration, and (3) extracellular fibrillar deposits in exfoliation syndrome, the most common recognizable cause of glaucoma, suggesting that both diseases may originate from similar misfolding mechanisms. A presentation of common pathogenetic pathways associated with these disorders, including cell death mechanisms, reactive oxygen species (ROS) production, mitochondrial dysfunction and vascular abnormalities, will serve as an initiation point for further exploration.
PMID: 23733125
ISSN: 1057-0829
CID: 670862

Biochemical analysis of myoglobinuria associated with rhabdomyolysis

Rostagno, Agueda; Ghiso, Jorge
ISSN: 0325-2957
CID: 575902

TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer's Abeta

Fossati, S; Ghiso, J; Rostagno, A
Vascular deposition of amyloid-beta (Abeta) in sporadic and familial Alzheimer's disease, through poorly understood molecular mechanisms, leads to focal ischemia, alterations in cerebral blood flow, and cerebral micro-/macro-hemorrhages, significantly contributing to cognitive impairment. Here, we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors DR4 and DR5 specifically mediate oligomeric Abeta induction of extrinsic apoptotic pathways in human microvascular cerebral endothelial cells with activation of both caspase-8 and caspase-9. The caspase-8 inhibitor cellular FLICE-like inhibitory protein (cFLIP) is downregulated, and mitochondrial paths are engaged through BH3-interacting domain death agonist (Bid) cleavage. Upregulation of DR4 and DR5 and colocalization with Abeta at the cell membrane suggests their involvement as initiators of the apoptotic machinery. Direct binding assays using receptor chimeras confirm the specific interaction of oligomeric Abeta with DR4 and DR5 whereas apoptosis protection achieved through RNA silencing of both receptors highlights their active role in downstream apoptotic pathways unveiling new targets for therapeutic intervention.
PMID: 22695614
ISSN: 2041-4889
CID: 169523

Amyloid beta oligomers trigger death receptors-mediated apoptosis in cerebral endothelial cells [Meeting Abstract]

Fossati, S; Ghiso, J; Rostagno, A
Vascular deposition of Abeta in sporadic and familial Alzheimer's disease, through poorly understood molecular mechanisms, leads to alterations in cerebral blood flow, focal ischemia, and cerebral micro-/macro-hemorrhages, significantly contributing to cognitive impairment. We aimed to determine the molecular mechanisms triggering apoptosis of vessel wall cells in presence of Abeta40 or its vasculotropic variants E22Q or L34V. Challenging human brain microvascular endothelial cells with both variants and wild-type Abeta40, we showed that TRAIL death receptors DR4 and DR5 specifically mediate oligomeric Abeta induction of extrinsic apoptotic pathways. Caspase-8 activation preceded activation of caspase-9. The caspase-8 inhibitor cFLIP was downregulated, and mitochondrial paths were engaged through BID cleavage. Up-regulation of DR4 and DR5 and co-localization with Abeta at the cell membrane suggested their involvement as initiators of the apoptotic machinery. Direct binding assays using receptor chimeras confirmed the specific interaction of oligomeric Abeta with DR4 and DR5 whereas apoptosis protection achieved through RNA silencing of both receptors highlighted their active role in downstream apoptotic pathways unveiling new targets for therapeutic intervention
ISSN: 0892-6638
CID: 178108

Vasculotropic Abeta genetic variants and the activation of mitochondrial apoptotic pathways [Meeting Abstract]

Rostagno, A A
The vascular deposition of amyloid, known as cerebral amyloid angiopathy (CAA) is an age-associated condition and a common finding in Alzheimer's disease, in which Abeta vascular deposits are featured in[80% of the cases. Familial Abeta variants with substitutions at positions 21-23 are primarily associated with CAA, and they manifest clinically with striking phenotypes of cerebral hemorrhage or dementia. The more recently reported Piedmont AbL34V mutant, located outside the hot-spot 21-23, shows a similar hemorrhagic phenotype, albeit less aggressive than the widely studied Dutch AbetaE22Q variant. In spite of the clinical impact of CAA, very little is known about the mechanisms causing degeneration in vessel wall cells. Our studies monitored the apoptotic events triggered by Abeta in human cerebral microvascular cells. Structural analyses of the different Abeta homologues showed that apoptosis preceded fibril formation in all cases, correlating with the presence of oligomers and/ or protofibrils. Induction of analogous caspase-mediated mitochondrial pathways was elicited by all peptides, although within different time-frames and intensity. Vessel-wall cell death was prevented through pharmacological inhibition of mitochondrial cytochrome c release or by the action of pan- and pathway-specific caspase inhibitors, giving clear indication of the independent or synergistic engagement of both extrinsic and intrinsic apoptotic mechanisms. Activation of caspase 8, usually triggered by death receptors, preceded that of caspase 9 while pathway specific PCR arrays demonstrated the involvement of TNF-receptor family members. Overall, our data suggests a primary involvement of death receptors in Abeta-induced vascular cell apoptosis supporting the notion that rare genetic mutations constitute unique paradigms to understand the molecular pathogenesis of CAA
ISSN: 1029-8428
CID: 158618

Search for amyloid-binding proteins by affinity chromatography

Calero, Miguel; Rostagno, Agueda; Ghiso, Jorge
'Amyloid binging proteins' is a generic term used to designate proteins that interact with different forms of amyloidogenic peptides or proteins and that, as a result, may modulate their physiological and pathological functions by altering solubility, transport, clearance, degradation, and fibril formation. We describe a simple affinity chromatography protocol to isolate and characterize amyloid-binding proteins based on the use of sequential elution steps that may provide further information on the type of binding interaction. As an example, we depict the application of this protocol to the study of Alzheimer's amyloid beta (Abeta) peptide-binding proteins derived from human plasma. Biochemical analysis of the proteins eluted under different conditions identified serum amyloid P component (SAP) and apolipoprotein J (clusterin) as the main plasma Abeta-binding proteins while various apolipoproteins (apoA-IV, apoE, and apoA-I), as well as albumin (HSA) and fibulin were identified as minor contributors.
PMID: 22528093
ISSN: 1064-3745
CID: 264122