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Retina and Brain Display Early and Differential Molecular and Cellular Changes in the 3xTg-AD Mouse Model of Alzheimer’s Disease

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Abstract

The concept 'the retina as a window to the brain' has been increasingly explored in Alzheimer´s disease (AD) in recent years, since some patients present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by noninvasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD; males), this study was undertaken to investigate whether the retina and brain (hippocampus and cortex) undergo similar molecular and cellular changes during the early stages (4 and 8 months) of the pathology, and if the retina can anticipate the alterations occurring in the brain. We assessed amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier integrity, cell death, neurotransmitter levels, and glial changes. Overall, the retina, hippocampus, and cortex of 3xTg-AD are not significantly affected at these early stages. However, we detected a few differential changes in the retina and brain regions, and particularly a different profile in microglia branching in the retina and hippocampus, only at 4 months, where the number and length of the processes decreased in the retina and increased in the hippocampus. In summary, at the early stages of pathology, the retina, hippocampus, and cortex are not significantly affected but already present some molecular and cellular alterations. The retina did not mirror the changes detected in the brain, and these observations should be taking into account when using the retina as a potential diagnostic tool for AD.

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Data Availability

Raw data files are available upon request.

Code Availability

Not applicable.

Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer´s disease

AP:

Alkaline phosphatase

APP:

Amyloid precursor protein

BACE:

Beta-secretase

BBB:

Blood–brain barrier

BCA:

Bicinchoninic acid

BRB:

Blood–retinal barrier

BSA:

Bovine serum albumin

CNS:

Central nervous system

ChAT:

Choline acetyltransferase

DAPI:

6-Diamidino-2-phenylindole

DOC:

Sodium deoxycholate

DTT:

Dithiothreitol

ECF:

Chemifluorescence

ECL:

Chemiluminescence

EDTA:

Ethylenediaminetetraacetic acid

EGTA:

Ethylene glycol tetraacetic acid

GABA:

Gamma-aminobutyric acid

GFAP:

Glial fibrillary acidic protein

HBSS:

Hank’s balanced salt solution

HPLC:

High-performance liquid chromatography

HRP:

Horseradish peroxidase

Iba-1:

Ionized calcium-binding adapter molecule 1

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate buffer saline

PFA:

Paraformaldehyde

PMSF:

Phenylmethylsulfonyl fluoride

PSD95:

Postsynaptic density protein 95

p-tau:

Phosphorylated tau

PVDF:

Polyvinylidene difluoride

RGCs:

Retinal ganglion cells

RT:

Room temperature

SDS:

Sodium dodecyl sulfate

THB:

Tissue homogenization buffer

vGlut1:

Vesicular glutamate transporter type I

WT:

Wild-type

TJ:

Tight junctions

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

ZO-1:

Zonula occludens-1

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Funding

Santa Casa Mantero Belard Award 2015 (MB-1049-2015), Foundation for Science and Technology (PEst UID/NEU/04539/2013 and UID/NEU/04539/2019: CNC.IBILI; PEst UIDB/04539/2020 and UIDP/04539/2020: CIBB), COMPETE-FEDER (POCI-01-0145-FEDER-007440), and Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000008: BrainHealth 2020).

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Authors and Affiliations

  1. Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Ana Catarina Rodrigues-Neves, Rafael Carecho, Elisa Julião Campos, Filipa Isabel Baptista & António Francisco Ambrósio

  2. Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal

    Ana Catarina Rodrigues-Neves, Rafael Carecho, Sónia Catarina Correia, Cristina Carvalho, Elisa Julião Campos, Filipa Isabel Baptista, Paula Isabel Moreira & António Francisco Ambrósio

  3. Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal

    Ana Catarina Rodrigues-Neves, Rafael Carecho, Sónia Catarina Correia, Cristina Carvalho, Elisa Julião Campos, Filipa Isabel Baptista, Paula Isabel Moreira & António Francisco Ambrósio

  4. Center for Neuroscience and Cell Biology (CNC), Coimbra, Portugal

    Sónia Catarina Correia, Cristina Carvalho & Paula Isabel Moreira

  5. Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal

    Elisa Julião Campos & António Francisco Ambrósio

  6. Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Paula Isabel Moreira

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  1. Ana Catarina Rodrigues-Neves
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  5. Elisa Julião Campos
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  8. António Francisco Ambrósio
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Contributions

ACRN, RC, and AFA conceived and designed the experiments. ACRN, RC, SCC, CC, EJC, and FIB performed the experiments. ACRN, RC, SCC, CC, EJC, FIB, PIM, and AFA analyzed the results. PIM and AFA contributed with reagents/materials/analysis tools. ACRN wrote the first draft of the manuscript, and all authors have read and approved the final version.

Corresponding author

Correspondence to António Francisco Ambrósio.

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Ethics Approval

All experiments using animals were approved by the Animal Welfare (Órgão Responsável pelo Bem-Estar Animal - ORBEA 16/2015) of the Coimbra Institute for Clinical and Biomedical research (iCBR), Faculty of Medicine, University of Coimbra, and by Direção Geral de Alimentação e Veterinária (DGAV 0421/000/000/2015) and conducted in accordance with the European Community directive guidelines for the use of animals in laboratory (2010/63/EU) transposed to the Portuguese law in 2013 (Decreto-Lei 113/2013), and in agreement with the Association for Research in Vision and Ophthalmology statement for animal use.

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Not applicable.

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All authors have reviewed and approved the manuscript.

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The authors declare no conflict of interest.

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Rodrigues-Neves, A.C., Carecho, R., Correia, S.C. et al. Retina and Brain Display Early and Differential Molecular and Cellular Changes in the 3xTg-AD Mouse Model of Alzheimer’s Disease. Mol Neurobiol 58, 3043–3060 (2021). https://doi.org/10.1007/s12035-021-02316-x

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