The Development of Signs of Alzheimer’s Disease in OXYS Rats is Accompanied by a Decrease in the Expression of Cerebral Dopamine Neurotrophic Factor (CDNF), and is not Compensated by Its Overexpression

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease leading to senile dementia. It is known that the processes of neurodegeneration are closely related to neurotrophic support. In this work, carried out on a model of AD - the OXYS line of rapidly aging rats, CDNF deficiency in the hippocampus was first identified, and an attempt was made to compensate for it by inducing overexpression using an adeno-associated viral construct. The constructs were introduced into the dorsal hippocampus of rats at the age of three months. 15 months after the introduction of the construct, we showed overexpression of CDNF in the target structure, but did not detect its effect on the learning and memory of animals in the Morris water maze, as well as on the accumulation of Aβ and Tau protein and the expression of genes involved in the unfolded protein response (UPR).

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About the authors

Ya. P. Kaminskaya

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

T. V. Ilchibaeva

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

T. A. Kozlova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

N. G. Kolosova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

V. S. Naumenko

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

A. S. Tsybko

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

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2. Fig. 1. Experimental design

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3. Fig. 2. CDNF expression in the hippocampus of OXYS and Wistar rats at 20 days, 3.5 months and 18 months of age: a - mRNA level of Cdnf gene; b - quantification of chemiluminescent signal intensity for CDNF protein and the result of membrane immunoblot. The number of cDNA copies of the gene is referred to per 100 copies of rPol2a cDNA. Protein levels are presented in relative units normalised to the corresponding GAPDH level. * p < 0.05; ** p < 0.01 - compared to control

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4. Fig. 3. CDNF overexpression in the hippocampus of OXYS rats. a - co-localisation of calreticulin and transduced CDNF in the CA1 region of the hippocampus (scale bar - 100 μm). Hippocampal slices were subjected to immunohistochemical staining for detection of CDNF (green) and calreticulin (red) followed by confocal microscopy. Nuclei are shown in blue. Colocalisation is shown in yellow. b, mRNA level of the Cdnf gene; c, quantification of chemiluminescent signal intensity for CDNF protein and the result of immunoblot on the membrane. The number of cDNA copies of the gene is referred to per 100 copies of rPol2a cDNA. Protein levels are presented in relative units normalised to the corresponding GAPDH level. * p < 0.05; *** p < 0.005 - compared to control

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5. Fig. 4. a - Latent time of platform finding in the ‘Morris water maze’ test for animals with CDNF overexpression and animals of the control group; b - Control test to check the quality of spatial memory formation. Time (%) spent in the target sector (Ts.): compared to the opposite sector (Pr.) and compared to a 25% probability of being in the target sector at random (indicated by the dashed line). ** p < 0.01; * p < 0.05 for AAV-CDNF group compared to AAV-EGFP group

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6. Fig. 5. Expression of Mapt (a), App (d), and Cdk5 (e) genes. The mRNA level is represented as the number of gene copies attributed per 100 copies of rPol2. Quantification of chemiluminescent signal intensity for protein, and membrane immunoblot results for TAU (b), pTAU (c), APP (e), CDK5 (g), pCDK5 (Tyr15) (h), pCDK(Ser159) (i). Protein levels are presented in relative units normalised to the corresponding GAPDH level

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