Aging and Parkinson's disease (PD). Aging is the primary risk factor for PD. Despite reported success with neurotrophic or neuroprotective therapeutic drugs or cell replacement therapies in animal models of PD, none have led to a clinically effective treatment avenue, curing all aspects of the disease complex. Since aging is the number one risk factor for PD, it must be considered in designing appropriate animal models. The studies proposed herein are unique in that we utilize aging as an important aspect of our models, many studies have shown that the aged ?environment? may be a critical factor in response to therapeutics. Inflammation and Parkinson?s disease. Inflammation in the brain, in particular, activation of microglia has been increasingly associated with the ongoing pathogenesis of PD, as well as several other neurodegenerative disorders. An area that has not been widely considered is that innate immune function is profoundly impacted by aging. We have demonstrated profound changes in proteomic profiles of microglia with age, and others have examined genomic alterations as well. We have recently demonstrated that some anti-inflammatory approaches to treat PD models that are successful in young animals, are not as efficacious in aged animals. Pointing to an important role of aging as a factor involved in disease progression and the response to therapeutics. Exosomes are powerful genomic modulators of inflammation: Human adipose-derived stem cells (hASC?s) manifest a secretome that is capable of modulating the environment of the host. Among these secreted molecules, small membrane-bound vesicles known as exosomes can modulate immune function as part of their mechanism of action following both brain injury and epilepsy. Exosomes contain long non coding RNA (lncRNA) that act as genomic modulators. Exosomes are an ideal vector for delivery of neuroprotective agents because of their unique ability to hone to tissues, and their increased stability compared to un-encapsulated RNA. Further, we have evidence that they modulate inflammation at the genomic level, making them a powerful tool to explore as a therapeutic in PD Aging impacts microglial phenotype, reducing the efficacy some therapeutics. It is our hypothesis, that hASC exosomes alter microglial function at a genomic level by delivery of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and other important factors, thus making them ideal for use in aged subjects. We will explore this by isolating microglia from young and aged rats, treated with and without intranasal hASC exosomes and perform advanced mass spectrometry based phenotypic profiling. We will characterize microglia proteomic profiles during progression of an AAV9-a-synuclein model of PD in young and aged rats. We hypothesize that hASDCexo will modulate the progression of PD pathology by interacting with the innate immune system at the genomic level. Many therapeutic approaches focused on altering innate immune function have been successful in reducing pathology from a-synuclein, including our studies with CX3CL1. We hypothesize that hASCexo will reduce PD pathology by a modulating microglial gene expression. We will examine this using intranasal delivery of hASCexo in an AAV9-Syn model of PD. We further predict retained efficacy of exosomes in aged rats in modulating progression of PD pathology.
Aging and Parkinson's disease (PD). Aging is the primary risk factor for PD. Despite reported success with neurotrophic or neuroprotective therapeutic drugs or cell replacement therapies in animal models of PD, none have led to a clinically effective treatment avenue, curing all aspects of the disease complex. Inflammation in the brain, in particular, activation of microglia has been increasingly associated with the ongoing pathogenesis of PD. Aging impacts immune cell phenotype, reducing the efficacy some therapeutics. We have identified exosomes derived from human adipose derived stem cells as a potent modulator of inflammation. Exosomes are an ideal vector for delivery of neuroprotective agents because of their unique ability to home to tissues, and their increased stability compared to un-encapsulated RNA. This project seeks to establish exosomes as a therapeutic alternative for PD.
| Grimmig, Beth; Daly, Lauren; Subbarayan, Meena et al. (2018) Astaxanthin is neuroprotective in an aged mouse model of Parkinson's disease. Oncotarget 9:10388-10401 |
| Nash, Kevin R; Moran, Peter; Finneran, Dylan J et al. (2015) Fractalkine over expression suppresses ?-synuclein-mediated neurodegeneration. Mol Ther 23:17-23 |
| Shahaduzzaman, Md; Nash, Kevin; Hudson, Charles et al. (2015) Anti-human ?-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-?-synuclein rat model of Parkinson's disease. PLoS One 10:e0116841 |
