Dataset Information

Amyloid ? perturbs elevated heme flux induced with neuronal development.

ABSTRACT: Introduction:Heme is a central molecule in mitochondrial respiration and ATP generation in neuronal cells. Thus, we assessed the importance of altered heme metabolism in Alzheimer's disease (AD) pathogenesis. Methods:To investigate the role of altered heme metabolism in AD, we identified heme-related proteins whose expression is altered in AD patients and mouse models exhibiting amyloid pathology. We detected the levels of proteins involved in heme synthesis, uptake, degradation, and function during neuronal differentiation and characterized the effects of A?. Results:We found that the expression levels of the rate-limiting heme synthetic enzyme ALAS1 and heme degradation enzyme HO-2 are selectively decreased in AD patients and mice. A? selectively reduces the levels of HO-2 and heme degradation, which are elevated to support neuronal functions in fully differentiated neuronal cells. Discussion:Our data show that lowered heme metabolism, particularly the decreased levels of heme degradation and HO-2, is likely a very early event in AD pathogenesis.

SUBMITTER: Vidal C

PROVIDER: S-EPMC6352316 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Amyloid β perturbs elevated heme flux induced with neuronal development.

Vidal Chantal C Daescu Kelly K Fitzgerald Keely E KE Starokadomska Anna A Bezprozvanny Ilya I Zhang Li L

Alzheimer's & dementia (New York, N. Y.) 20190122

<h4>Introduction</h4>Heme is a central molecule in mitochondrial respiration and ATP generation in neuronal cells. Thus, we assessed the importance of altered heme metabolism in Alzheimer's disease (AD) pathogenesis.<h4>Methods</h4>To investigate the role of altered heme metabolism in AD, we identified heme-related proteins whose expression is altered in AD patients and mouse models exhibiting amyloid pathology. We detected the levels of proteins involved in heme synthesis, uptake, degradation, ...[more]

PMID: 30723777

Similar Datasets

Project description:Disruption of functional connectivity between brain regions may represent an early functional consequence of ?-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Project description:Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (A?) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane glycoproteins expressed by all higher organisms, including two mammalian orthologs (APLP1 and APLP2) that have complicated investigations into the specific activities of APP. By comparison, insects express only a single APP-related protein (APP-Like, or APPL) that contains the same protein interaction domains identified in APP. However, unlike its mammalian orthologs, APPL is only expressed by neurons, greatly simplifying an analysis of its functions in vivo. Like APP, APPL is processed by secretases to generate a similar array of extracellular and intracellular cleavage fragments, as well as an A?-like fragment that can induce neurotoxic responses in the brain. Exploiting the complementary advantages of two insect models (Drosophila melanogaster and Manduca sexta), we have investigated the regulation of APPL trafficking and processing with respect to different aspects of neuronal development. By comparing the behavior of endogenously expressed APPL with fluorescently tagged versions of APPL and APP, we have shown that some full-length protein is consistently trafficked into the most motile regions of developing neurons both in vitro and in vivo. Concurrently, much of the holoprotein is rapidly processed into N- and C-terminal fragments that undergo bi-directional transport within distinct vesicle populations. Unexpectedly, we also discovered that APPL can be transiently sequestered into an amphisome-like compartment in developing neurons, while manipulations targeting APPL cleavage altered their motile behavior in cultured embryos. These data suggest that multiple mechanisms restrict the bioavailability of the holoprotein to regulate APPL-dependent responses within the nervous system. Lastly, targeted expression of our double-tagged constructs (combined with time-lapse imaging) revealed that APP family proteins are subject to complex patterns of trafficking and processing that vary dramatically between different neuronal subtypes. In combination, our results provide a new perspective on how the regulation of APP family proteins can be modulated to accommodate a variety of cell type-specific responses within the embryonic and adult nervous system.

Dataset Information

Amyloid ? perturbs elevated heme flux induced with neuronal development.

Publications

Amyloid β perturbs elevated heme flux induced with neuronal development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure