L-DOPA regulates neuroinflammation and Aβ pathology through NEP and ADAM17 in a mouse model of AD

Abstract

Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.

Keywords: Alzheimer’s disease; Aβ; L-DOPA; Neuroinflammation; Tau.

Fig. 1

L-DOPA treatment significantly suppresses micro/astrogliosis and Aβ plaque deposition in 5xFAD mice. Four-month-old 5xFAD mice were injected with vehicle (0.9% saline, i.p.) or L-DOPA + benserazide (10 mg/kg and 2.5 mg/kg, respectively, i.p.) daily for 15 days. A Immunofluorescence staining of Iba-1. B Quantification of data in A (n = 28 brain slices from 7 mice/group). C Immunofluorescence staining of GFAP. D Quantification of data in C (n = 28 brain slices from 7 mice/group). E, G Immunofluorescence staining of 6E10. F, H Quantification of data in E, G (n = 27–28 brain slices from 7 mice/group). I, K, M Immunofluorescence staining of NEP. J, L, N Quantification of data in I, K, M (n = 27–28 brain slices from 7 mice/group). O, Q, S Immunofluorescence staining of ADAM17. P, R, T Quantification of data in O, Q, S (n = 27–28 brain slices from 7 mice/group). *<0.05, **p < 0.01, ***p < 0.001. Scale bar = 100 µm