Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amy... more Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amyloid Abeta11-42 was relatively abundant in two cases of familial Alzheimer's disease involving two distinct mutations in beta-APP. However, four important differences should be borne in mind: the authors compare Abeta11-42 with Abeta1-42 and ignore Abeta1-40, although both Abeta1-40 and Abeta1-42 are generated by beta-secretase/BACE cleavage
Mutations in the gene encoding the protein presenilin-1 are the most common cause of familial Alz... more Mutations in the gene encoding the protein presenilin-1 are the most common cause of familial Alzheimer's disease and they often produce a different disease course from sporadic Alzheimer's and another familial form associated with mutations in the gene encoding beta-amyloid precursor protein. Here we show that a peculiar form of beta-amyloid that is devoid of the first ten amino acids accumulates in the brains of patients carrying presenilin-1 mutations, and is more abundant than in subjects affected by the other types of Alzheimer's.
The conversion of the prion protein (PrP) into a protease-resistant isoform (PrP(Res)) is conside... more The conversion of the prion protein (PrP) into a protease-resistant isoform (PrP(Res)) is considered the pathogenic event responsible for prion encephalopathies. Microglia activation accompanies PrP(Res) deposition representing an early event in the progression of these diseases. It is now believed that microglial cells play a worsening, if not causative, role in prion-induced neuronal death, through the release of proinflammatory and neurotoxic molecules. Indeed, in vitro observations have demonstrated that PrP(Res) and the synthetic prion fragment PrP106-126 induce neuronal death by activating microglial to migrate in the lesion area and secrete cytokines. Recently, we and others have demonstrated that the recombinant peptide, corresponding to the protease-resistant portion of PrP encompassing the amino acids 90-231 (PrP90-231), when beta-structured, is toxic for neuronal cells, in vitro. Here we report that PrP90-231 induces activation of N9 microglial cells, characterized by cell proliferation arrest and increased secretion of different cytokines (RANTES, GCSF, and IL-12). Moreover, the treatment of N9 cells with PrP90-231 elicited inducible nitric oxide synthase (i-NOS) expression, nitric oxide release, and a delayed (15 min to 1 h of treatment) extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation/activation. Although ERK1/2 is known to regulate proliferative and differentiative events, we show that its blockade, using the specific MEK inhibitor PD98059, did not prevent PrP90-231-induced inhibition of N9 cell proliferation. To our knowledge, this is the first evidence that a recombinant PrP(Res)-like peptide elicits microglial activation in vitro, thus representing a potentially important tool to develop possible therapeutic strategies to target prion-induced brain inflammation.
Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amy... more Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amyloid Abeta11-42 was relatively abundant in two cases of familial Alzheimer's disease involving two distinct mutations in beta-APP. However, four important differences should be borne in mind: the authors compare Abeta11-42 with Abeta1-42 and ignore Abeta1-40, although both Abeta1-40 and Abeta1-42 are generated by beta-secretase/BACE cleavage
Mutations in the gene encoding the protein presenilin-1 are the most common cause of familial Alz... more Mutations in the gene encoding the protein presenilin-1 are the most common cause of familial Alzheimer's disease and they often produce a different disease course from sporadic Alzheimer's and another familial form associated with mutations in the gene encoding beta-amyloid precursor protein. Here we show that a peculiar form of beta-amyloid that is devoid of the first ten amino acids accumulates in the brains of patients carrying presenilin-1 mutations, and is more abundant than in subjects affected by the other types of Alzheimer's.
The conversion of the prion protein (PrP) into a protease-resistant isoform (PrP(Res)) is conside... more The conversion of the prion protein (PrP) into a protease-resistant isoform (PrP(Res)) is considered the pathogenic event responsible for prion encephalopathies. Microglia activation accompanies PrP(Res) deposition representing an early event in the progression of these diseases. It is now believed that microglial cells play a worsening, if not causative, role in prion-induced neuronal death, through the release of proinflammatory and neurotoxic molecules. Indeed, in vitro observations have demonstrated that PrP(Res) and the synthetic prion fragment PrP106-126 induce neuronal death by activating microglial to migrate in the lesion area and secrete cytokines. Recently, we and others have demonstrated that the recombinant peptide, corresponding to the protease-resistant portion of PrP encompassing the amino acids 90-231 (PrP90-231), when beta-structured, is toxic for neuronal cells, in vitro. Here we report that PrP90-231 induces activation of N9 microglial cells, characterized by cell proliferation arrest and increased secretion of different cytokines (RANTES, GCSF, and IL-12). Moreover, the treatment of N9 cells with PrP90-231 elicited inducible nitric oxide synthase (i-NOS) expression, nitric oxide release, and a delayed (15 min to 1 h of treatment) extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation/activation. Although ERK1/2 is known to regulate proliferative and differentiative events, we show that its blockade, using the specific MEK inhibitor PD98059, did not prevent PrP90-231-induced inhibition of N9 cell proliferation. To our knowledge, this is the first evidence that a recombinant PrP(Res)-like peptide elicits microglial activation in vitro, thus representing a potentially important tool to develop possible therapeutic strategies to target prion-induced brain inflammation.
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