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

Larson, Megan; Greimel, Susan; Amar, Fatou; LaCroix, Michael; Boyle, Gabriel; Sherman, Mathew A.; Schley, Hallie; Miel, Camille; Schneider, Julie A.; Kayed, Rakez; Benfenati, Fabio; Lee, Michael K.; Bennett, David A.; Lesné, Sylvain

doi:10.1073/pnas.1704698114

Cited by 52 publications

(79 citation statements)

References 80 publications

(111 reference statements)

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“…Fig. 1 (Online Resource 1); as previously reported [30]). However, examination of amyloid burden at 6 months of age, when amyloid deposition is limited to the hippocampus in APP mice [36], revealed striking differences using two antibodies detecting Aβ (Fig.…”

Section: Resultssupporting

confidence: 66%

“…5, 6 (Online Resources 5 and 6)). As previously described [30], the conformational state of αSyn in intracellular-enriched fractions was assayed by dot blotting using two αSyn antibodies, Syn33 and F8H7, each of which recognizes a distinct set of oligomers. Total and human-specific αSyn were also assayed on dot blots using 4D6 and LB509 antibodies, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5c (Online Resource 5)), suggesting that αSyn and Aβ species recognized by these broad-spectrum antibodies were not interacting. Finally, to determine the relative size of αSyn species contributing to the increased signal with 4D6 and LB509 antibodies, we performed western blotting analyses as recently described by our group [30]. In our hands, Syn33 and F8H7 were not compatible for western blot analyses (they both fail to differentiate αSyn-KO from other mouse lines; data not shown) and were therefore omitted by design.…”

Section: Resultsmentioning

confidence: 99%

“…Triple-label immunofluorescence was performed as previously described [30] using Alexa Fluor ™ -488, -555, -647–conjugated secondary antibodies (Molecular Probes, Invitrogen), treated for autofluorescence with 0.1% Sudan Black solution, and coverslipped with ProLong-DAPI mounting medium (Molecular Probes). Digital images were obtained using an Olympus IX81 FluoView1000 microscope.…”

Section: Methodsmentioning

confidence: 99%

“…Soluble multimeric Aβ and tau assemblies, or oligomers, coordinately promote synapse loss, memory deficiencies, and ectopic neuronal cell cycle re-entry (CCR), a precursor to neuron death in AD [6, 37, 44, 45, 48]. Alongside Aβ and tau, soluble alpha-synuclein (αSyn) is also strongly linked to memory deficits in AD, as well as in Parkinson’s disease (PD) and Lewy body dementia (LBD) [1, 3, 18, 30, 40], suggesting an intrinsic contribution of αSyn to brain pathophysiology. However, the conformational state(s) and functions of soluble αSyn is particularly unclear in AD.…”

Section: Introductionmentioning

confidence: 99%

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Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

et al. 2018

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α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

et al. 2018

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Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

et al. 2018

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Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent α-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in α-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from α-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) α-synuclein overexpression (AAV-hαsyn). We found that Syn III ko mice injected with AAV-hαsyn did not develop fibrillary insoluble α-synuclein aggregates, showed reduced amount of α-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated α-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-hαsyn injection. Our observations indicate that Syn III constitutes a crucial mediator of α-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.

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Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy

et al. 2019

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Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s disease-linked human mutant A53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expression or accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02032-w) contains supplementary material, which is available to authorized users.

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

Cited by 52 publications

References 80 publications

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy

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