Inhibition of amyloid-β plaque formation by α-synuclein

Bachhuber, Teresa; Katzmarski, Natalie; McCarter, Joanna F; Loreth, Desirée; Tahirović, Sabina; Kamp, Frits; Abou‐Ajram, Claudia; Nuscher, Brigitte; Serrano-Pozo, Alberto; Müller, Alexandra; Prinz, Marco; Steiner, Harald; Hyman, Bradley T.; Haass, Christian; Meyer‐Luehmann, Melanie

doi:10.1038/nm.3885

Cited by 100 publications

(97 citation statements)

References 42 publications

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“…First, recent studies reported that the overexpression of the A30P mutant of human αSyn in APP/PS1 Tg mice, another model of AD, led to a lowering of Aβ deposition and to synaptic abnormalities suggestive of synapse loss (53). The alterations in synaptic proteins observed in 3-mo-old bigenic J20×TgI2.2 mice appear reminiscent of those reported by Bachhuber et al despite qualitative differences.…”

Section: Synapsin-i/ii Lowering and Cognitive Deficits In Ad And Animalmentioning

confidence: 61%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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Section: Synapsin-i/ii Lowering and Cognitive Deficits In Ad And Animalmentioning

confidence: 61%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In vitro data show an induction of abeta aggregation by alpha-synuclein 7 . In contrast, a more recent study detected decreased abeta deposits due to injection of alpha-synuclein containing homogenates or preformed alpha-synuclein fibrils in hippocampus of an AD mouse model 8 . However, cross-seeding activity of alpha-synuclein has been hypothesized to be the molecular consequence of alphasynuclein inclusions in 60% of AD patients 4,9 .…”

mentioning

confidence: 71%

Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization

Helferich

McLean

Weishaupt

et al. 2016

J Neurol Neuromedicine

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Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue. Furthermore we comment on the reported alpha-synuclein-induced SOD1 polymerization in terms of cross-seeding effects in neurodegeneration. CommentaryRecently, we presented evidence for a so far unknown interaction of alpha-synuclein and SOD1 with potential pathophysiological relevance 1 . Abnormal protein deposits of alphasynuclein characterize synucleinopathies, a group of neurodegenerative diseases including PD, dementia with Lewy bodies and multiple system atrophy, whereas SOD1 is associated with the pathogenesis of ALS. Mutations in SOD1 lead to ALS and protein aggregates containing SOD1 in a subset of ALS patients.Our recent study indicates that alpha-synuclein and SOD1 influence each other's aggregation tendency. Using a protein complementation assay, alpha-synuclein was found to increase SOD1 dimerization. Although homodimers of SOD1 are enzymatically active, alpha-synuclein does not seem to change the enzyme activity of SOD1 1 . Alpha-synuclein might induce the formation of either inactive SOD1 dimers or higher molecular aggregates of SOD1 which are thought to be enzymatically inactive 2 . Additional support for an influencing role of alpha-synuclein on the aggregation property of SOD1 comes from the study by Koch et al. 3 . Here, the authors demonstrated that preformed recombinant alphasynuclein fibrils added to the cell culture media of SOD1 transfected cells induced the polymerization of SOD1. The same was also observed in vivo when recombinant preformed alpha-synuclein fibrils were injected in the temporal cortex of SOD1 G93A transgenic mice.

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“…The reason for this is unclear, but one possibility is that the injections of α-synuclein-containing preparations inhibit plaque formation in the brains of Aβ precursor protein transgenic mice, as recently shown in basic research [30]. Aβ fibril formation was also reduced in the presence of α-synuclein in an in vitro aggregation assay.…”

Section: Discussionmentioning

confidence: 94%

“…However, FBB likely does not bind to the nonfibrillar oligomeric forms of Aβ, which have been suggested as being more toxic than the Aβ plaques in the pathogenesis of AD-related neuronal dysfunction and memory deficits [40]. The inhibition of Aβ fibril formation and deposition can increase toxic Aβ oligomers, thereby leading to neurodegeneration despite reduced Aβ plaque load [30]. Thus, it is premature to conclude that Aβ toxicity does not contribute to cognitive impairment in PD with negative amyloid PET results.…”

Section: Discussionmentioning

confidence: 99%

Extremely Low Prevalence of Amyloid Positron Emission Tomography Positivity in Parkinson's Disease without Dementia

Mashima¹,

Ito²,

Kameyama

et al. 2017

Eur Neurol

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Background: Most cases of dementia with Lewy bodies (DLB) show Alzheimer's disease pathology-like senile plaques and neurofibrillary tangles. Several studies have also revealed a high prevalence of positive amyloid imaging with positron emission tomography (PET) in DLB and moderate prevalence in Parkinson's disease (PD) with dementia. However, it remains unclear in PD without dementia as to when the brain β amyloid (Aβ) burden begins and progresses. Our study aimed to determine the prevalence of Aβ deposition in PD without dementia using amyloid PET. Methods: This was a cross-sectional study on 33 patients with PD without dementia, of whom 21 had normal cognition and 12 met the criteria for PD-mild cognitive impairment. All subjects underwent neuropsychological assessment and [¹⁸F] florbetaben (FBB) PET. Results: All subjects had Lewy body-related disorders, displaying a significantly reduced myocardial [¹²³I] metaiodobenzylguanidine uptake. The cortical FBB-binding pattern in all subjects, including APOE e4 carriers, suggested negative Aβ deposition. Conclusion: Patients with PD without dementia exhibit an extremely low prevalence of Aβ positivity compared with those reported in cognitively normal elderly controls. Further longitudinal imaging studies and long-term follow-up are needed; however, our findings provide novel insights for understanding Aβ metabolism in PD.

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Inhibition of amyloid-β plaque formation by α-synuclein

Cited by 100 publications

References 42 publications

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization

Extremely Low Prevalence of Amyloid Positron Emission Tomography Positivity in Parkinson's Disease without Dementia

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