The Retinal Dopaminergic Circuit as a Biomarker for Huntington's and Alzheimer's Diseases

Abstract

Retinal dysfunction is emerging as a potential early marker of neurodegenerative diseases. Within the retina, the dopaminergic circuit, comprising dopaminergic amacrine cells, dopamine synthesis and turnover, and dopamine receptor signalling, is essential for visual processing, particularly colour contrast perception. Disruption of this circuit may underline early retinal alterations observed in Huntington's disease (HD) and Alzheimer's disease (AD). In this study, we systematically analysed retinal dopaminergic dysfunction in murine models of HD (genetic origin) and AD (sporadic), across different disease stages. We assessed dopamine levels, turnover, tyrosine hydroxylase expression, D1 and D2 receptor gene expression, and neurotransmitter balance. HD mice showed early and marked alterations: reduced dopamine content, decreased tyrosine hydroxylase, increased turnover, and downregulation of D1 receptor expression-all preceding motor symptoms and detectable brain pathology. In contrast, AD mice showed only mild changes at later stages; however, clinical evidence suggests that similar dysfunction may occur earlier in human AD. These findings position retinal dopaminergic disruption as a potential early biomarker in HD and possibly in AD. While the current study relies on invasive techniques in animal models, it lays the groundwork for non-invasive retinal assessments, such as electroretinography or optical coherence tomography, as promising tools for early diagnosis and disease monitoring in neurodegeneration.

Keywords: Alzheimer’s disease; Huntington’s disease; colour contrast; dopaminergic circuit; retina.

Figure 1

Retinal dopaminergic circuit. The circuit starts with the dopaminergic amacrine cells (DACs) that release dopamine (DA) to the photoreceptors (expressing dopamine receptor 4 (D4R)), to the cone bipolar cells (expressing dopamine receptor 1 (D1R)), to the horizontal cells (expressing D1R), to the amacrine cells AII (expressing D1R), and to the retinal ganglion cells (RGCs, expressing D1R and D2R). DACs also express D2R as an autoreceptor to control the DA release.

Figure 2

Catecholamines and TH levels in HD mice retinas. (A) DA levels were measured by HPLC (n = 7–8). (B) TH levels were measured by western blot and normalized to their actin levels. The graph represents the value of bands’ densitometry in arbitrary units (a.u) (n = 6–11). (C) Representation of ratio DOPAC+HVA/DA (n = 4–11). ns = non-significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.005.

Figure 3

Gene expression of dopamine receptors in HD mice retinas. (A) mRNA levels of D1R normalized to GAPDH mRNA (n = 4–5). (B) mRNA levels of D2R normalized to GAPDH mRNA (n = 4–5). ns = non significant, * = p < 0.05, ** = p < 0.01.

Figure 4

Catecholamines and TH levels in AD mice retinas. (A) DA levels were measured by HPLC (n = 7–9). (B) Representation of the ratio DOPAC+HVA/DA (n = 8–9). (C) TH levels were measured by western blot and the data were normalized to their actin levels (n = 7–9). ns= non-significant, * = p < 0.05, *** = p < 0.005.

Figure 5

Gene expression of D1R and D2R of AD mice retinas. (A) mRNA levels of D1R are shown and normalized to GAPDH mRNA levels (n = 4). (B) mRNA levels of D2R are shown and normalized to GAPDH mRNA (n = 3–4). ns = non-significant, * = p < 0.05.

Figure 6

Excitatory and inhibitory neurotransmitter levels in the retinas of HD mice. (A) Ratio of glutamate (GLU) to the sum of inhibitory neurotransmitters GABA and glycine (GLY), indicating overall excitatory/inhibitory balance (n = 7–8). (B) Absolute levels of glutamate (n = 8–11). ns: no significant differences were found. ns = non-significant, * = p < 0.05.

Figure 7

Excitatory and inhibitory neurotransmitter levels in the retinas of AD mice. (A) Ratio of glutamate (GLU) to the sum of inhibitory neurotransmitters GABA and glycine (GLY), reflecting the excitatory/inhibitory balance (n = 7–9). (B) Absolute glutamate levels (n = 7–8). ns = non-significant; * = p < 0.05, ** = p < 0.01.