Retinal ganglion cells (RGCs) can develop tau-linked pathology in neurodegenerative disorders, including Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration. Because the retina is accessible to non-invasive imaging, tau-associated RGC injury is a candidate biomarker for disease staging and monitoring.
RGCs are projection neurons whose axons form the optic nerve and transmit visual signals to central targets.[1] In tauopathy contexts, RGC dysfunction reflects both local retinal stress and systems-level neurodegenerative processes involving axonal transport, neuroinflammation, and synaptic injury.[2][3]
RGC somas reside in the ganglion cell layer, with dendrites in the inner plexiform layer and long myelinated axons extending to thalamic and midbrain nuclei.[1:1] Their long axons and high metabolic demand make them sensitive to cytoskeletal and mitochondrial injury.[3:1][4]
Common RGC-associated markers include BRN3A/BRN3B, RBPMS, and neurofilament proteins; these are frequently used in imaging-pathology correlation studies.[1:2][5]
Studies report hyperphosphorylated tau epitopes (for example AT8/PHF1-reactive species), dystrophic neurites, and reduced RGC layer thickness in AD-spectrum cohorts.[6][7] Similar 4R-tau-driven processes are biologically plausible in PSP/CBD, where shared tau mechanisms can involve visual and oculomotor circuits.[2:1][8]
Optical coherence tomography (OCT), OCT angiography, and advanced retinal imaging provide quantitative readouts (RNFL/GCL thickness, microvascular metrics) that can track neurodegenerative change longitudinally.[7:2][11]
Retina-based readouts are attractive because they are repeatable, scalable, and potentially sensitive to early neurodegenerative changes before severe disability.[11:1][12]
RGC tauopathy can be used as a pharmacodynamic window for therapies targeting tau phosphorylation, tau propagation, mitochondrial dysfunction, and neuroinflammation.[2:3][3:3] Integrating retinal biomarkers with tau PET and fluid biomarkers may improve monitoring in CBS/PSP trials.[8:1][12:1]
Sanes JR, Masland RH. The types of retinal ganglion cells: current status and implications for neuronal classification. Annu Rev Neurosci. 2015. ↩︎ ↩︎ ↩︎
Stamelou M, Respondek G, Giagkou N, et al. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol. 2023. ↩︎ ↩︎ ↩︎ ↩︎
Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retin Eye Res. 2012. ↩︎ ↩︎ ↩︎ ↩︎
Osborne NN, Núñez-Álvarez C, del Olmo-Aguado S, Merrayo-Lloves J. Visual light effects on mitochondria and neuroprotection in retinal ganglion cells. Prog Retin Eye Res. 2017. ↩︎ ↩︎
Nadal-Nicolás FM, Salinas-Navarro M, Jiménez-López M, et al. Displaced retinal ganglion cells in albino and pigmented rats. Front Neuroanat. 2014. ↩︎
den Haan J, Verbraak FD, Visser PJ, Bouwman FH. Retinal thickness in Alzheimer's disease: A systematic review and meta-analysis. Alzheimers Dement (Amst). 2017. ↩︎
London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol. 2013. ↩︎ ↩︎ ↩︎
Dickson DW, Ahmed Z, Algom AA, et al. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol. 2010. ↩︎ ↩︎
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016. ↩︎ ↩︎
Alavi MV, Fuhrmann N. Dominant optic atrophy, OPA1, and mitochondrial quality control. Prog Retin Eye Res. 2013. ↩︎ ↩︎
Lim JKH, Li QX, He Z, et al. The eye as a biomarker for Alzheimer's disease. Front Neurosci. 2016. ↩︎ ↩︎
Chan VTT, Sun Z, Tang S, et al. Spectral-domain OCT measurements in Alzheimer's disease and mild cognitive impairment. Ophthalmology. 2019. ↩︎ ↩︎