Pathological Interface Between Oligomeric Alpha-Synuclein and Tau in Synucleinopathies

Sengupta, Urmi; Guerrero-Muñoz, Marcos J.; Castillo-Carranza, Diana L.; Lasagna‐Reeves, Cristian A.; Gerson, Julia E.; Paulucci-Holthauzen, Adriana; Krishnamurthy, Shashirekha; Farhed, Malika; Jackson, George R.; Kayed, Rakez

doi:10.1016/j.biopsych.2014.12.019

Cited by 144 publications

(144 citation statements)

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“…S4). Each fraction was subjected to a panel of commercially available antibodies detecting human αSyn (LB509, 4B12), mouse/human αSyn (4D6), phosphorylated and misfolded αSyn (pS129-αSyn and Syn514), and to a panel of antibodies generated to detect oligomeric and aggregated amyloid proteins (A11, OC, Officer), including o-αSyn (Syn33, F8H7) (23). We also included analyses with the 6E10 antibody detecting Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] to determine whether the putative o-αSyn might be coupled to Aβ as a hybrid oligomer (24).…”

Section: Resultsmentioning

confidence: 99%

“…S4A). To confirm that these species corresponded to αSyn oligomers, we used antibodies detecting various oligomers of amyloid proteins (i.e., A11, OC, Officer) (25,26), as well as antibodies specific to o-αSyn, Syn33, and F8H7 (23). OC and Officer detected fibrillar amyloid species cosegregating with the 35-kDa/72-kDa αSyn molecules in both AD and TgI2.2 samples, suggesting that the αSyn forms detected in SEC fraction 38 were prefibrillar oligomeric αSyn assemblies.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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.

Self Cite

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“…Membranes were washed with Trisbuffered saline (20 mM Tris, 0.8% NaCl, pH7.4, with 0.006% Tween 20; TBST) and blocked with Blocker Blotto in TBS (Life Technologies) for 1 h, washed 3 times for 10 min in TBST, and allowed to incubate with the primary antibody, anti-tau oligomeric antibody T22 (Blair et al, 2013;Sengupta et al, 2015) or the oligomerspecific antibody A11 (Shin et al, 2008) for 1-2 h, followed by 3 10 min washes. An HRPconjugated secondary antibody was allowed to incubate for 1 h and developed using chemiluminescence for detection of signal (Lumigold; SignaGen Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Hunt¹,

Nash

Placides³

et al. 2015

J. Neurosci.

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Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for L-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV-tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

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“…Upon clinical diagnosis of PD, the loss in dopaminergic neurons has already reached 80%, and thus neuroprotective therapies for PD are of little significance as the majority of dopaminergic neurons are lost. By contrast, the use of regenerative agents in PD patients appears to be more promising (4). Cell-based therapy has been advocated for PD due to the high failure rate of other therapeutic strategies (5).…”

Section: Effect Of Intranasal Stem Cell Administration On the Nigrostmentioning

confidence: 99%

Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease

Salama

Sobh

Emam

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5x10 5 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.

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Pathological Interface Between Oligomeric Alpha-Synuclein and Tau in Synucleinopathies

Cited by 144 publications

References 70 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

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease

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