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Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer’s disease


Carrero, Laura; Antequera, Desireé; Alcalde, Ignacio; Megías, Diego; Figueiro-Silva, Joana; Merayo-Lloves, Jesús; Municio, Cristins; Carro, Eva (2023). Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer’s disease. Acta Neuropathologica Communications, 11(1):55.

Abstract

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.

Abstract

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Pathology and Forensic Medicine
Health Sciences > Neurology (clinical)
Life Sciences > Cellular and Molecular Neuroscience
Uncontrolled Keywords:Cellular and Molecular Neuroscience, Neurology (clinical), Pathology and Forensic Medicine, Alzheimer’s disease, Circadian rhythm, Clock genes, Retina, Transgenic mice, Retinal ganglion cells, Retinohypothalamic tract, Hypothalamus, Amyloid, Melanopsin
Language:English
Date:31 March 2023
Deposited On:16 Apr 2023 15:48
Last Modified:29 Apr 2024 01:37
Publisher:BioMed Central
ISSN:2051-5960
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/s40478-023-01529-6
PubMed ID:37004084
Other Identification Number:PMCID: PMC10067208
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)