Multimodal evaluation of the melanopsin retinal ganglion cells system in relation to circadian rhythms in Alzheimer’s disease and aging

Background: Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide. This neurodegenerative syndrome affects cognition, memory, behavior, and the visual system, particularly the retina. Objective: This work aims to determine whether the 5xFAD mouse, a transgenic model of AD, displays changes in the function of retinal ganglion cells (RGCs) and if those alterations are correlated with changes in the expression of glutamate and gamma-aminobutyric acid (GABA) neurotransmitters. Methods: In young (2–3-month-old) and adult (6-7-month-old) 5xFAD and WT mice, we have studied the physiological response, firing rate, and burst of RGCs to various types of visual stimuli using a multielectrode array system. Results: The firing rate and burst response in 5xFAD RGCs showed hyperactivity at the early stage of AD in young mice, whereas hypoactivity was seen at the later stage of AD in adults. The physiological alterations observed in 5xFAD correlate well with an increase in the expression of glutamate in the ganglion cell layer in young and adults. GABA staining increased in the inner nuclear and plexiform layer, which was more pronounced in the adult than the young 5xFAD retina, altering the excitation/inhibition balance, which could explain the observed early hyperactivity and later hypoactivity in RGC physiology. Conclusion: These findings indicate functional changes may be caused by neurochemical alterations of the retina starting at an early stage of the AD disease.

Download Full-text

Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01094-2 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Ryan J. Bevan ◽

Tim R. Hughes ◽

Pete A. Williams ◽

Mark A. Good ◽

B. Paul Morgan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Dependent Manner ◽

Retinal Ganglion ◽

Brain Pathology ◽

Cell Degeneration ◽

Non Invasive

AbstractNeuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer’s disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer’s disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer’s progression. However, the extent of retinal involvement in Alzheimer’s models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer’s mouse models, Tg2576, 3xTg-AD and APPNL-G-F. Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer’s models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer’s models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer’s disease.

Download Full-text

Salvage of the retinal ganglion cells in transition phase in Alzheimer’s disease with topical coenzyme Q10: is it possible?

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-019-04544-3 ◽

2019 ◽

Vol 258 (2) ◽

pp. 411-418

Author(s):

Refika Hande Karakahya ◽

Tuba Şaziye Özcan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Retinal Ganglion Cells ◽

Coenzyme Q10 ◽

Ganglion Cells ◽

Transition Phase ◽

Retinal Ganglion

Download Full-text

Photosensitive Melanopsin-Containing Retinal Ganglion Cells in Health and Disease: Implications for Circadian Rhythms

International Journal of Molecular Sciences ◽

10.3390/ijms20133164 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3164 ◽

Cited By ~ 11

Author(s):

Pedro Lax ◽

Isabel Ortuño-Lizarán ◽

Victoria Maneu ◽

Manuel Vidal-Sanz ◽

Nicolás Cuenca

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Well Being ◽

Average Density ◽

Retinal Ganglion ◽

Healthy Humans ◽

Cell Alterations ◽

Circadian Rhythm Disorders

Melanopsin-containing retinal ganglion cells (mRGCs) represent a third class of retinal photoreceptors involved in regulating the pupillary light reflex and circadian photoentrainment, among other things. The functional integrity of the circadian system and melanopsin cells is an essential component of well-being and health, being both impaired in aging and disease. Here we review evidence of melanopsin-expressing cell alterations in aging and neurodegenerative diseases and their correlation with the development of circadian rhythm disorders. In healthy humans, the average density of melanopsin-positive cells falls after age 70, accompanied by age-dependent atrophy of dendritic arborization. In addition to aging, inner and outer retinal diseases also involve progressive deterioration and loss of mRGCs that positively correlates with progressive alterations in circadian rhythms. Among others, mRGC number and plexus complexity are impaired in Parkinson’s disease patients; changes that may explain sleep and circadian rhythm disorders in this pathology. The key role of mRGCs in circadian photoentrainment and their loss in age and disease endorse the importance of eye care, even if vision is lost, to preserve melanopsin ganglion cells and their essential functions in the maintenance of an adequate quality of life.

Download Full-text

Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms

PLoS ONE ◽

10.1371/journal.pone.0003153 ◽

2008 ◽

Vol 3 (9) ◽

pp. e3153 ◽

Cited By ~ 96

Author(s):

Didem Göz ◽

Keith Studholme ◽

Douglas A. Lappi ◽

Mark D. Rollag ◽

Ignacio Provencio ◽

...

Keyword(s):

Circadian Rhythms ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion

Download Full-text

Ganglion Cell Layer Thinning in Alzheimer’s Disease

Medicina ◽

10.3390/medicina56100553 ◽

2020 ◽

Vol 56 (10) ◽

pp. 553

Author(s):

Alicia López-de-Eguileta ◽

Andrea Cerveró ◽

Ainara Ruiz de Sabando ◽

Pascual Sánchez-Juan ◽

Alfonso Casado

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ganglion Cell Layer ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Preclinical Ad ◽

Future Direction ◽

The Impact

The main advantages of optical retinal imaging may allow researchers to achieve deeper analysis of retinal ganglion cells (GC) in vivo using optical coherence tomography (OCT). Using this device to elucidate the impact of Alzheimer’s disease (AD) on retinal health with the aim to identify a new AD biomarker, a large amount of studies has analyzed GC in different stages of the disease. Our review highlights recent knowledge into measuring retinal morphology in AD making distinctive between whether those studies included patients with clinical dementia stage or also mild cognitive impairment (MCI), which selection criteria were applied to diagnosed patients included, and which device of OCT was employed. Despite several differences, previous works found a significant thinning of GC layer in patients with AD and MCI. In the long term, an important future direction is to achieve a specific ocular biomarker with enough sensitivity to reveal preclinical AD disorder and to monitor progression.

Download Full-text