Dataset Information

Alzheimer's-related peptide amyloid-? plays a conserved role in angiogenesis.

ABSTRACT: Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-? (A?). Early versions of the amyloid hypothesis considered A? something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation--over three hundred million years--indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how A? regulates blood vessel branching in tissues as varied as human umbilical vein and zebrafish hindbrain. High physiological concentrations of A? monomer induced angiogenesis by a conserved mechanism that blocks ?-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize ?-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration.

SUBMITTER: Cameron DJ

PROVIDER: S-EPMC3392248 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alzheimer's-related peptide amyloid-β plays a conserved role in angiogenesis.

Cameron D Joshua DJ Galvin Cooper C Alkam Tursun T Sidhu Harpreet H Ellison John J Luna Salvadore S Ethell Douglas W DW

PloS one 20120709 7

Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-β (Aβ). Early versions of the amyloid hypothesis considered Aβ something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation--over three hundred million years--indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how Aβ regulates blood vessel branc ...[more]

PMID: 22792182

Similar Datasets

Project description:The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that ?-amyloid (A?) accumulation is a key element. It follows that clearing the brain of A? would be beneficial, which has not been the case. Therefore, A? is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor ?-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with A?. Protein data bank (pdb) entries for klotho and A? were searched on the RCSB Protein Data Bank for ?-KL and AD amyloid ?-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the A? and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of A?. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of A? suggests that A? can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

Dataset Information

Alzheimer's-related peptide amyloid-? plays a conserved role in angiogenesis.

Publications

Alzheimer's-related peptide amyloid-β plays a conserved role in angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets