Amyloid β(1–42) and its β(25–35) fragment induce activation and membrane translocation of cytosolic phospholipase A2 in bovine retina capillary pericytes

Anfuso, Carmelina Daniela; Assero, Giovanna; Lupo, Gabriella; Nicotra, Ambra; Cannavò, Giuseppe; Strosznajder, Robert P.; Rapisarda, Piero; Pluta, Ryszard; Alberghina, Mario

doi:10.1016/j.bbalip.2004.09.006

Cited by 33 publications

(22 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, A␤ peptides activate cPLA 2 (36,37), which is concentrated at the pre-synaptic membrane (29,52), and pharmacological inhibition of cPLA 2 protects against A␤-induced synapse damage (29) and ameliorates cognitive impairment in a mouse model of AD (38). Here, we show that A␤ activates synaptic cPLA 2 in Prnp (ϩ/ϩ) neurons but had a lesser effect on synapses in Prnp (0/0) neurons.…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

Amyloid-β-induced Synapse Damage Is Mediated via Cross-linkage of Cellular Prion Proteins

Bate

Williams

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cellular prion protein (PrP C ), which is highly expressed at synapses, was identified as a receptor for the amyloid-␤ (A␤) oligomers that are associated with dementia in Alzheimer disease. Here, we report that A␤ oligomers secreted by 7PA2 cells caused synapse damage in cultured neurons via a PrP C -dependent process. Exogenous PrP C added to Prnp knock-out (0/0) neurons was targeted to synapses and significantly increased A␤-induced synapse damage. In contrast, the synapse damage induced by a phospholipase A 2 -activating peptide was independent of PrP C . In Prnp wild-type (؉/؉) neurons A␤ oligomers activated synaptic cytoplasmic phospholipase A 2 (cPLA 2 ). In these cells, the addition of A␤ oligomers triggered the translocation of cPLA 2 in synapses to cholesterol dense membranes (lipid rafts) where it formed a complex also containing A␤ and PrP C . In contrast, the addition of A␤ to Prnp (0/0) neurons did not activate synaptic cPLA 2 , which remained in the cytoplasm and was not associated with A␤. Filtration assays and non-denaturing gels demonstrated that A␤ oligomers cross-link PrP C . We propose that it is the cross-linkage of PrP C by A␤ oligomers that triggers abnormal activation of cPLA 2 and synapse damage. This hypothesis was supported by our observation that monoclonal antibody mediated cross-linkage of PrP C also activated synaptic cPLA 2 and caused synapse damage. Alzheimer disease (AD)2 is a complex neurological disorder characterized by a progressive dementia resulting from synaptic failure (1, 2). The amyloid hypothesis maintains that the pivotal event in AD is the production and accumulation of amyloid-␤ (A␤) peptides following the proteolytic cleavage of the amyloid precursor protein (3-5). Disease-associated mutations result in the increased production of the 42-amino acid peptide fragment (A␤ 42 ) (6, 7), synthetic and recombinant forms of which acts as toxins. A␤ 42 peptides self-aggregate and are found in multiple conformations ranging from small oligomers to larger fibrils and plaques. The soluble A␤ oligomers that are considered to be the principal mediators of neurotoxicity (8 -11) demonstrate disease-specific accumulation in the brain (12) and bind to synapses (13,14). The high potency of A␤ oligomers suggests that their effects are mediated through specific receptors. The cellular prion protein (PrP C ) that is highly expressed at synapses (15, 16) was recently identified as a receptor that mediates A␤-induced inhibition of synaptic plasticity and impaired memory in a model of AD (17). However, the role of PrP C in AD pathogenesis has been challenged by others who reported that A␤ caused memory deficits in mice in the absence of PrP C (18, 19). Such apparently contradictory findings might be explained by the use of synthetic A␤ peptides, which were combined with different models of memory formation as surrogates of dementia. Studies that use synthetic A␤ preparations may be compromised by their propensity to self-aggregate into a wide variety of oligomer sizes and conformation...

show abstract

Section: Discussionmentioning

confidence: 76%

“…For example, A␤ peptides activate cPLA 2 (36,37), and pharmacological inhibition of cPLA 2 protects against A␤-induced synapse damage (29) and ameliorates cognitive impairment in a mouse model of AD (38). For these reasons, the effects of A␤ 42 on synaptic cPLA 2 in Prnp (ϩ/ϩ) and Prnp (0/0) neurons were investigated.…”

Section: Prpmentioning

confidence: 99%

Amyloid-β-induced Synapse Damage Is Mediated via Cross-linkage of Cellular Prion Proteins

Bate

Williams

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…-amyloid cerebral vessel accumulation is antiangiogenic, too (Paris et al, 2004b). Ischemic-and -amyloiddependent changes in pericytes (Lupo et al, 2001;Anfuso et al, 2004) and astrocytes (Pluta 2002a;Pluta 2002b;Pluta 2003) could influence angiogenesis and could cause the dysfunction of bloodbrain barrier (Ramsauer et al, 2002). According recent data processes influencing angiogenesis can also regulate neurogenesis in brain (Carmeliet 2003).…”

Section: Kind Of Changes Ischemic Brain Referencesmentioning

confidence: 94%

Role of Ischemic Blood-Brain Barrier on Amyloid Plaques Development in Alzheimers Disease Brain

Pluta

2007

CNR

Self Cite

View full text Add to dashboard Cite

This review demonstrated that ischemic brain injury induces chronic changes in blood-brain barrier in the gray and white matter. This insufficiency of blood-brain barrier may allow entry of uncellular blood components such as different fragments of amyloid precursor protein and cellular blood components like leukocytes and platelets into the brain parenchyma. These blood components may have chronic harmful effects on the ischemic neuronal cells, axons and myelin and can intensify and finish the neuropathology in ischemic brain parenchyma. Pathological accumulation of different toxic fragments of amyloid precursor protein in extracellular space and myelinated axons appears after ischemic blood-brain barrier injury and seem to be concomitant with, but independent of neuronal ischemic cytoplasmic injury. It seems that ischemic blood-brain barrier disturbances may play an important, both direct and indirect role in the pathogenesis of extra- and intracellular space in gray and white matter lesions following ischemic episode. This neuropathology appears to have similar character and distribution as in sporadic Alzheimer's disease. This review presented chronic micro-blood-brain barrier openings in ischemic gray and white matter lesions that probably would act as seeds of future Alzheimer's amyloid plaques.

show abstract

“…This type of correlation between p70S6K phosphorylation and tau phosphorylation at the S262 in relationship to Ab has not been reported before. Several previous studies have demonstrated that Ab25-35 has a similar toxic effect on cells as Ab1-40/42 [19,[21][22][23]]. In the current study, treating wild-type N2a with 25 lM Ab25-35 resulted in a significant increase of pp70S6K at the T421/S424 sites at 4 h and 12 h, and the T389 site at 4 h. The coinciding increase in the level of p-tau at the S262 site at 4 h and 12 h similar to the level of p-p70S6K at T421/S424 sites suggests that p70S6K activity towards tau at the S262 site is more likely mediated by the signaling events that regulate T421/S424 phosphorylation than those regulating the T389 site [5][6][7][8].…”

mentioning

confidence: 99%

Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

2007

View full text Add to dashboard Cite

This study set out to search for a link between overproduction of Ab and p70S6 kinase (p70S6K) phosphorylation/ activation. Results showed that levels of p-p70S6K at T421/ S424 and T389 are significantly increased in mouse N2a neuroblastoma cells carrying human APP with Swedish mutation (APPswe), and in transgenic APPswe/PS1 (A246E) mice as compared with respective controls, corresponding to the increase of tau phosphorylation at S262. This parallel increase in p70S6K activation and tau phosphorylation could be demonstrated by treating wild-type N2a cells with Ab25-35. Our results suggest that the Ab deposition in senile plaques in Alzheimer disease brains might be a primary event that activates p70S6K and phosphorylates tau at S262, resulting in microtubule disruption.

show abstract

Amyloid β(1–42) and its β(25–35) fragment induce activation and membrane translocation of cytosolic phospholipase A2 in bovine retina capillary pericytes

Cited by 33 publications

References 48 publications

Amyloid-β-induced Synapse Damage Is Mediated via Cross-linkage of Cellular Prion Proteins

Amyloid-β-induced Synapse Damage Is Mediated via Cross-linkage of Cellular Prion Proteins

Role of Ischemic Blood-Brain Barrier on Amyloid Plaques Development in Alzheimers Disease Brain

Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

Contact Info

Product

Resources

About