Protein transduction domain peptide mediates delivery to the brain via the blood-brain barrier in Drosophila melanogaster

Саранцева, С. В.; Bolshakova, O. I.; Тимошенко, С. И.; Kolobov, A. A.; Vitek, Michael P.; Schwarzman, A. L.

doi:10.1134/s199075080902005x

Cited by 6 publications

(8 citation statements)

References 30 publications

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“…A major obstacle in this approach is the limited penetration of peptides into the brain. Therefore, we fused the COG133 apoE-peptide with penetratin to generate COG112 [22] , which was previously successfully tested for the transport of cargo across the BBB in Drosophila and rodents [31] , [32] , [49] , [50] . We tested these peptides in elav; APP/BACE and elav;BACE/APP-Sw lines that display age-progressive neurodegeneration and strong declines in cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

et al. 2009

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BackgroundMutations of the amyloid precursor protein gene (APP) are found in familial forms of Alzheimer's disease (AD) and some lead to the elevated production of amyloid-β-protein (Aβ). While Aβ has been implicated in the causation of AD, the exact role played by Aβ and its APP precursor are still unclear.Principal FindingsIn our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Aβ. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies.ConclusionsThe development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE) with neuroprotective activities.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

et al. 2009

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“…Furthermore, these studies highlight that the entire holoprotein of an apolipoprotein does not necessarily need to be present in order to confer a beneficial effect, and it is conceivable that future research may identify small functional peptides derived from ApoD and ApoJ [247]. In addition, technology is currently being developed that aims to promote the transport of therapeutic peptides across the BBB and make them more resistant to degradation [247][248][249][250]. Gene expression values that are less than 60 are below the limit of reliable detection, and genes with expression values in this range are, therefore, considered not to be expressed in the brain.…”

Section: Future Perspectivementioning

confidence: 99%

Apolipoproteins in the brain: implications for neurological and psychiatric disorders

Elliott

Weickert

Garner

2010

Clinical Lipidology

172

171

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The brain is the most lipid-rich organ in the body and, owing to the impermeable nature of the blood-brain barrier, lipid and lipoprotein metabolism within this organ is distinct from the rest of the body. Apolipoproteins play a well-established role in the transport and metabolism of lipids within the CNS; however, evidence is emerging that they also fulfill a number of functions that extend beyond lipid transport and are critical for healthy brain function. The importance of apolipoproteins in brain physiology is highlighted by genetic studies, where apolipoprotein gene polymorphisms have been identified as risk factors for several neurological diseases. Furthermore, the expression of brain apolipoproteins is significantly altered in several brain disorders. The purpose of this article is to provide an up-to-date assessment of the major apolipoproteins found in the brain (ApoE, ApoJ, ApoD and ApoA-I), covering their proposed roles and the factors influencing their level of expression. Particular emphasis is placed on associations with neurological and psychiatric disorders. Keywords apolipoprotein; brain; CNS; lipid; neurological disease Structure & function of apolipoproteinsThe definition of 'apolipoprotein' can be some-what misleading. Textbooks and medical dictionaries tend to define apolipoproteins as "Any of various proteins that combine with a lipid to form a lipoprotein, such as HDL and LDL" [301], or "The protein components of lipoproteins, which remain after the lipids to which the proteins are bound have been removed" [302]. However, there are apolipoproteins, such as ApoD and Apo(a), that are not capable of forming even a nascent lipoprotein particle on their own, but rather associate with lipoproteins via hydrophobic surface features or through disulfide linkage to another Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. We should also acknowledge that a great volume of data related to apolipoprotein mRNA or protein expression, especially when the human brain is considered, may only be relevant for a specific brain region at a specific time in development or aging. Related to this, we have assembled apolipoprotein gene microarray data from a study, first described by Weickert et al. in 2009 [6], accessible at the National Center for Biotechnology Information Gene Expression Omnibus data-base [7,8,303], which highlights the dramatic changes in the expression of the quantitatively major apolipoproteins expressed in the human brain ( Figures 1-5). These data indicate that, of the 22 apolipoprotein genes analyzed in the prefrontal cortex, only three (APOD [ Figure 3C], APOE [ Figure 3D] and CLU [ Figure 4C]) are expressed at high levels. Furthermore, the expression of all three of ...

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“…; Sarantseva et al . ). On the C‐terminus, we fused the PKA inhibitory peptide, PKI, to our therapeutic peptide.…”

Section: Discussionmentioning

confidence: 97%

The design and delivery of a PKA inhibitory polypeptide to treat SCA1

Hearst

Shao

Lopez

et al. 2014

Journal of Neurochemistry

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Spinocerebellar ataxia-1 (SCA1) is a neurodegenerative disease that primarily targets Purkinje cells (PCs) of the cerebellum. The exact mechanism of PC degeneration is unknown, however, it is widely believed that mutant ataxin-1 becomes toxic because of the phosphorylation of its serine 776 (S776) residue by cAMP-dependent protein kinase A (PKA). Therefore, to directly modulate mutant ATXN1 S776 phosphorylation and aggregation, we designed a therapeutic polypeptide to inhibit PKA. This polypeptide comprised of a thermally responsive elastin-like peptide (ELP) carrier, which increases peptide half-life, a PKA inhibitory peptide (PKI), and a cell-penetrating peptide (Synb1). We observed that our therapeutic polypeptide, Synb1-ELP-PKI, inhibited PKA activity at concentrations similar to the PKI peptide. Additionally, Synb1-ELP-PKI significantly suppressed mutant ATXN1 S776 phosphorylation and intranuclear inclusion formation in cell culture. Further, Synb1-ELP-PKI treatment improved SCA1 PC morphology in cerebellar slice cultures. Furthermore, the Synb1-ELP peptide carrier crossed the blood-brain barrier and localized to the cerebellum via the i.p. or intranasal route. Here, we show the intranasal delivery of ELP-based peptides to the brain as a novel delivery strategy. We also demonstrate that our therapeutic polypeptide has a great potential to target the neurotoxic S776 phosphorylation pathway in the SCA1 disease.

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Protein transduction domain peptide mediates delivery to the brain via the blood-brain barrier in Drosophila melanogaster

Cited by 6 publications

References 30 publications

Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

Apolipoproteins in the brain: implications for neurological and psychiatric disorders

The design and delivery of a PKA inhibitory polypeptide to treat SCA1

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