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Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic A? Oligomers in Cells.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the ?-amyloid peptide (A?), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble A? oligomers correlate with clinical symptoms associated with the disease. The A? sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM ?-helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and A? production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within A? species remains undefined. Here, we describe highly resistant A?42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to A?42, but not to A?40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G(29)XXXG(33) and G(38)XXXA(42) motifs dramatically affect the A? oligomerization process. G33 and G38 in these motifs are specifically involved in A? oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted A?42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these A?42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation.

SUBMITTER: Decock M

PROVIDER: S-EPMC4861705 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Aβ Oligomers in Cells.

Decock Marie M Stanga Serena S Octave Jean-Noël JN Dewachter Ilse I Smith Steven O SO Constantinescu Stefan N SN Kienlen-Campard Pascal P

Frontiers in aging neuroscience 20160510

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the β-amyloid peptide (Aβ), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble Aβ oligomers correlate with clinical symptoms associated with the disease. The Aβ sequence beg ...[more]

PMID: 27242518

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Project description:BackgroundAlzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

Dataset Information

Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic A? Oligomers in Cells.

Publications

Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Aβ Oligomers in Cells.

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