Immunization with amyloid beta (Aβ) peptides or passive immunization with antibodies against Aβ has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, microgliosis as ...well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood‐brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with Aβ before and after the onset of AD‐type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after Aβ immunization the immune system clears Aβ from sources in the brain as it would in peripheral organs lacking barriers. Once Aβ is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.— Dickstein, D. L., Biron, K. E., Ujiie, M., Pfeifer, C. G., Jeffries, A. R., Jefferies, W. A. Aβ peptide immunization restores blood‐brain barrier integrity in Alzheimer disease. FASEB J. 20, 426–433 (2006)
The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of diseases of the brain. Our previous studies showed that that a soluble form of melanotransferrin (MTf; ...Uniprot P08582; also known as p97, MFI2 and CD228), a mammalian iron-transport protein, is an effective carrier for delivery of drug conjugates across the BBB into the brain and was the first BBB targeting delivery system to demonstrate therapeutic efficacy within the brain. Here, we performed a screen to identify peptides from MTf capable of traversing the BBB. We identified a highly conserved twelve-amino acid peptide, termed MTfp, that retains the ability to cross the intact BBB intact and enter intacellular organelles within neurons, glia and microglia in the brain. This peptide may provide a platform for the transport of therapeutics to the CNS, and thereby offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.
The serine-threonine kinase Akt is a protooncogene involved in the regulation of cell proliferation and survival. Activation of Akt is initiated by binding to the phospholipid products of ...phosphoinositide 3-kinase at the inner leaflet of the plasma membranes followed by phosphorylation at Ser(473) and Thr(308). We have found that Akt is activated by Salmonella enterica serovar Typhimurium in epithelial cells. A bacterial effector protein, SigD, which is translocated into host cells via the specialized type III secretion system, is essential for Akt activation. In HeLa cells, wild type S. typhimurium induced translocation of Akt to membrane ruffles and phosphorylation at residues Thr(308) and Ser(473) and increased kinase activity. In contrast, infection with a SigD deletion mutant did not induce phosphorylation or activity although Akt was translocated to membrane ruffles. Complementation of the SigD deletion strain with a mutant containing a single Cys to Ser mutation (C462S), did not restore the Akt activation phenotype. This residue has previously been shown to be essential for inositol phosphatase activity of the SigD homologue, SopB. Our data indicate a novel mechanism of Akt activation in which the endogenous cellular pathway does not convert membrane-associated Akt into its active form. SigD is also the first bacterial effector to be identified as an activator of Akt.
The serine-threonine kinase Akt is a protooncogene involved in the regulation of cell proliferation and survival. Activation of Akt is initiated by binding to the phospholipid products of ...phosphoinositide 3-kinase at the inner leaflet of the plasma membranes followed by phosphorylation at Ser473 and Thr308. We have found that Akt is activated by Salmonella enterica serovar Typhimurium in epithelial cells. A bacterial effector protein, SigD, which is translocated into host cells via the specialized type III secretion system, is essential for Akt activation. In HeLa cells, wild typeS. typhimurium induced translocation of Akt to membrane ruffles and phosphorylation at residues Thr308 and Ser473 and increased kinase activity. In contrast, infection with a SigD deletion mutant did not induce phosphorylation or activity although Akt was translocated to membrane ruffles. Complementation of the SigD deletion strain with a mutant containing a single Cys to Ser mutation (C462S), did not restore the Akt activation phenotype. This residue has previously been shown to be essential for inositol phosphatase activity of the SigD homologue, SopB. Our data indicate a novel mechanism of Akt activation in which the endogenous cellular pathway does not convert membrane-associated Akt into its active form. SigD is also the first bacterial effector to be identified as an activator of Akt.
Immunization with amyloid beta (A{szligbeta}) peptides or passive immunization with antibodies against A{szligbeta} has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, ...microgliosis as well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood-brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with A{szligbeta} before and after the onset of AD-type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after A{szligbeta} immunization the immune system clears A{szligbeta} from sources in the brain as it would in peripheral organs lacking barriers. Once A{szligbeta} is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.--Dickstein, D. L., Biron, K. E., Ujiie, M., Pfeifer, C. G., Jeffries, A. R., Jefferies, W. A. A{szligbeta} peptide immunization restores blood-brain barrier integrity in Alzheimer disease.
Vascular dysfunction is a crucial pathological hallmark of Alzheimer's disease (AD). Studies have reported that beta amyloid (Aβ) causes increased blood vessel growth in the brains of AD mouse ...models, a phenomenon that is also seen in AD patients. This has given way to an alternative angiogenesis hypothesis according to which, increased leakiness in the blood vessels disrupts the blood‐brain barrier (BBB) and allows unwanted blood products to enter the brain causing progression of disease pathology, promoting amyloid clumping and aggregation along with impaired cerebral blood flow. Furthermore, the expression of melanotransferrin in AD model and patients may contribute to angiogenesis. The objective of this chapter is to attempt to establish a link between the vascular damage and AD pathology. Curbing the vascular changes and resulting damage seen in the brains of AD model mice and improving their cognition by treating with FDA‐approved anti‐angiogenic drugs may expedite the translational potential of this research into clinical trials in human patients. This direction into targeting angiogenesis will facilitate new preventive and therapeutic interventions for AD and related vascular diseases.
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