Retinal Inflammation in Alzheimer’s Disease
Chronic, low-grade inflammation is a typical sign of Alzheimer’s neuropathology (Akiyama et al., 2000). Neuroinflammation in AD is linked with increased astrocyte and microglia reactivity and neurotoxicity, Aβ and tau seeding and propagation, as well as with microglia-mediated synaptic pruning (Cardona et al., 2006; Wyss-Coray, 2006; Stevens et al., 2007; Fuhrmann et al., 2010; Lee et al., 2010; Wyss-Coray and Rogers, 2012; Hong et al., 2016; Salter and Stevens, 2017; Ising et al., 2019; Friker et al., 2020). As in the brain, some histological studies have implicated inflammation in the retina of AD patients (Liew et al., 1994; Blanks et al., 1996a; Grimaldi et al., 2018). This is particularly interesting as the eye has historically been considered an immune privileged site (Zhou and Caspi, 2010). In 1996, Blanks and colleagues discovered increased GFAP expression in retinal astrocytes and Müller cells in the GCL of AD retina, suggesting astrogliosis occurs in the retina of these patients (Blanks et al., 1996a). More recently, detrimental astrocyte and microglial activation was observed along with Aβ plaques, tau tangles, and neurodegeneration in postmortem retinal tissues of 6 AD patients as compared with 6 control subjects (Grimaldi et al., 2019). Notably, molecular mediators of innate immunity including interleukin-1β (IL-1β), complement component 3 (C3), osteopontin, and triggering receptor expressed on myeloid cells 2 were found to be upregulated in retinal tissues of AD patients (Grimaldi et al., 2019).
Although much work in larger retinal samples is needed to investigate the nature and potential mechanisms of retinal inflammation in human AD, various studies in animal models of AD have also provided evidence and insights into retinal inflammation in this disorder. Ning and colleagues first established the correlation of neurodegeneration and inflammation in the retina of ADtg mice (Ning et al., 2008). Other studies have shown increased microgliosis and astrocytosis, infiltration of lymphocytes and monocytes, and upregulation of monocyte chemoattractant protein-1 (MCP-1) in multiple layers of the retina and choroid (Ning et al., 2008; Liu et al., 2009; Perez et al., 2009; Yang et al., 2013; Edwards et al., 2014; Tsai et al., 2014; Antes et al., 2015; Gao et al., 2015; Pogue et al., 2015). A recent study in 3xTg AD mice has further described morphological changes in retinal microglia, including increased microglial cell number, soma size, retraction and reorientation of microglial processes, and change in cell locations (Salobrar-Garcia et al., 2020).
In general, retinal inflammation is implicated in multiple traditional retinal vascular and neurodegenerative disorders, including diabetic retinopathy (Tang and Kern, 2011; Semeraro et al., 2015; Rubsam et al., 2018), AMD (Knickelbein et al., 2015; Kauppinen et al., 2016), and glaucoma (Vohra et al., 2013). During the onset of disease pathogenesis, retinal inflammation is usually triggered by an imbalance of pro- versus anti-inflammatory molecules. This can be evoked by a wide spectrum of pathogenic pathways, including overproduction of reactive oxygen species, activation of NF-κB or protein kinase C pathways, inflammasome or microglial activation, advanced glycation end products, or shear pressure and leukocyte invasion due to retinal microvascular damage. In this context, the recent discovery of early retinal pericyte loss in MCI patients (Shi et al., 2020) suggests an early BRB disturbance and perhaps retinal microvascular leakage in AD pathogenesis that may be implicated in retinal inflammation. Future studies should evaluate BRB leakage and the potential relationship with imbalanced retinal inflammatory pathway activation and brain inflammation in AD. Findings from such studies could lead to the discovery of novel retinal biomarkers to facilitate AD detection and monitoring.