Abstract
The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson’s disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder
After observing the inhibitory effects of AT1 blockers on dopaminergic cell death and microglial response induced by αsyn overexpression, we investigated the effects of neuronal αsyn overexpression on the renin angiotensin system (RAS) pro-oxidative pro-inflammatory axis (Ang II/AT1/NADPH oxidase)
We observed that the AAV serotype 9 (AAV9)-synapsin-αsyn vector led to overexpression of α-syn in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which induced a marked dopaminergic neuron loss together with a concomitant microglial neuroinflammatory response
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The loss of dopaminergic neurons and alpha-synuclein (α-syn) accumulation are major hallmarks of the disease. The etiology of PD appears multifactorial and remains largely unknown. Regardless of the cause, it is known that oxidative stress (OS) and neuroinflammation are the major factors for progression of the disease [1,2,3]. Alpha-syn is a 140-amino-acid protein, predominantly located in the presynaptic terminals, and a major component of Lewy bodies. It has been associated to the regulation of neurotransmitter release, regulation of synaptic vesicles, and microtubule dynamics [4, 5]. The pathogenic role of insoluble α-syn is less known. Microglial activation has been suggested as a major mechanism of α-syn toxicity [6]
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Schedule a callMore From: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
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