A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

Gallardo, Gilbert; Schlüter, Oliver M.; Südhof, Thomas C.

doi:10.1038/nn2058

Cited by 131 publications

(128 citation statements)

References 47 publications

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“…The lateral ventricles of E15.5 embryos were injected with 2 lL Qiagen Maxiprep DNA and Fast Green dye using a pulled micropipette. The following plasmids were used: pCMV-LifeAct-TagRFP [51] (3 lg/lL; 60102, ibidi GmbH, Martinsried, Germany), GFP-actinin [52] (3 lg/lL), tdTomato [53] (0.5 lg/lL; 22478, Addgene, Cambridge, MA; originally named FUtdTW), and pCS2 min-GFP [49] (1 lg/lL). Forceps-type electrode paddles controlled by an ECM 830 electroporator (BTX Instrument Division, Harvard Apparatus Inc, Holliston, MA) were used to deliver 5 pulses at 60 mV with 50 ms duration at 100 ms intervals.…”

Section: In Utero Electroporationmentioning

confidence: 99%

“…To further investigate dynamic changes in F-actin during neurite initiation, we electroporated rat cortical neurons in utero with Lifeact-RFP, a red fluorescent protein (RFP)-tagged peptide with high affinity for F-actin [51]. Cultures were subsequently prepared from the P0 cortices of electroporated pups and live-imaged shortly after plating.…”

Section: Neurite Initiation Occurs At the Site Of Actin Aggregationmentioning

confidence: 99%

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Actin Aggregations Mark the Sites of Neurite Initiation

et al. 2016

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A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendrite morphogenesis, the early steps of neuritogenesis remain relatively unexplored. Here we showed that redistribution of cortical actin into large aggregates preceded neuritogenesis and determined the site of neurite initiation. Enhancing actin polymerization by jasplakinolide treatment effectively blocked actin redistribution and neurite initiation, while treatment with the actin depolymerizing agents latrunculin A or cytochalasin D accelerated neurite formation. Together, these results demonstrate a critical role of actin dynamics and reorganization in neurite initiation. Further experiments showed that microtubule dynamics and protein synthesis are not required for neurite initiation, but are required for later neurite stabilization. The redistribution of actin during early neuronal development was also observed in the cerebral cortex and hippocampus in vivo.

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Section: In Utero Electroporationmentioning

confidence: 99%

Section: Neurite Initiation Occurs At the Site Of Actin Aggregationmentioning

confidence: 99%

Actin Aggregations Mark the Sites of Neurite Initiation

et al. 2016

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“…ApoE appears to play a mechanistic role as plaques associated with AD are constructed of β-amyloid (Aβ) and apoE proteins (Nakamura et al 1996;Burns et al 2003). Similarly, interactions of increased apoE levels with alpha synuclein in the brain can lead to neuronal degeneration (Gallardo et al 2008).…”

mentioning

confidence: 99%

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Haley

Kohama

Urbanski

et al. 2010

AGE

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Loss of synaptic integrity in the hippocampus and prefrontal cortex (PFC) may play an integral role in age-related cognitive decline. Previously, we showed age-related increases in the dendritic marker microtubule associated protein 2 (MAP-2) and the synaptic marker synaptophysin (SYN) in mice. Similarly, apolipoprotein E (apoE), involved in lipid transport and metabolism, and glial fibrillary acidic protein (GFAP), a glia specific marker, increase with age in rodents. In this study, we assessed whether these four proteins show similar age-related changes in a nonhuman primate, the rhesus macaque. Freefloating sections from the PFC and hippocampus from adult, middle-aged, and aged rhesus macaques were immunohistochemically labeled for MAP-2, SYN, apoE, and GFAP. Protein levels were measured as area occupied by fluorescence using confocal microscopy as well as by Western blot. In the PFC and hippocampus of adult and middle-aged animals, the levels of SYN, apoE, and GFAP immunoreactivity were comparable but there was a trend towards higher MAP-2 levels in middle-aged than adult animals. There was significantly less SYN and more MAP-2, apoE, and GFAP immunoreactivity in the PFC and hippocampus of aged animals compared to adult or middle-aged animals. Thus, the age-related changes in MAP-2, apoE, and GFAP levels were similar to those previously observed in rodents. On the other hand, the age-related changes in SYN levels were not, but were similar to those previously observed in the aging human brain. Taken together, these data emphasize the value of the rhesus macaque as a pragmatic translational model for human brain aging.

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“…Lower apoE levels in the CSF of a PD animal model relative to normal animals have been documented [33]. In a transgenic mouse model of α-synuclein the deletion of apoE expression also decreased the levels of insoluble, in favour of soluble, α-synuclein and slowed the neurodegeneration [20]. The absolute intraneuronal levels of apoE in PD group are probably a more important consideration but unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In our findings, while low levels of apoE aggravated the extent of α-syn aggregation, the higher level tended to supress aggregation. Neurodegeneration induced by overexpressed α-syn in transgenic mice also caused higher levels of apoE [20]. (A-C) Effect of apoE isoforms at different concentrations of (A) apoE2, (B) apoE3 and (C) apoE4 on the kinetics of 50µM α-synuclein aggregation using sandwich capture immunoassay.…”

Section: Discussionmentioning

confidence: 99%

Effects of different isoforms of apoE on aggregation of the α‐synuclein protein implicated in Parkinson’s disease

Emamzadeh

Aojula

McHugh

2016

Neuroscience Letters

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Parkinson's disease is a progressive brain disorder due to the degeneration of dopaminergic neurons in the substantia nigra. Parkinson's disease is a progressive brain disorder due to the degeneration of dopaminergic neutrons in the SN. The accumulation of aggregated forms of α-synuclein protein into Lewy bodies is one of the characteristic features of this disease although the pathological role of any such protein deposits in causing neurodegeneration remains elusive. Here, the effects of different apolipoprotein E isoforms (apoE2, apoE3, apoE4) on the aggregation of α-synuclein in vitro were examined using thioflavin T assays and also an immunoassay to detect the formation of multimeric forms.Our results revealed that the aggregation of α-synuclein is influenced by apoE concentration. At low concentrations of apoE (<15 nM), all of the isoforms were able to increase the aggregation of α-synuclein (50 µM), with apoE4 showing the greatest stimulatory effect. This is in contrast to a higher concentration (>15 nM) of these isoforms, where a decrease in the aggregation of α-synuclein was noted. The data show that exceptionally low levels of apoE may seed α-syn aggregation, which could potentially lead to the pathogenesis of α-synuclein-induced neurodegeneration. On the other hand, higher levels of apoE could potentially lower the degree of α-synuclein aggregation and confer protection. The differential effects noted with apoE4 could explain why this particular isoform results in an earlier age of onset for Parkinson's disease.

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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

Cited by 131 publications

References 47 publications

Actin Aggregations Mark the Sites of Neurite Initiation

Actin Aggregations Mark the Sites of Neurite Initiation

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Effects of different isoforms of apoE on aggregation of the α‐synuclein protein implicated in Parkinson’s disease

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