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Impact of changes in neurotrophic supplementation on development of Alzheimer’s disease-like pathology in OXYS rats

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Abstract

Alzheimer’s disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75NTR, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development.

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Abbreviations

Aβ:

β-amyloid

AβPP:

Aβ precursor protein

AD:

Alzheimer’s disease

BDNF:

brain-derived neurotrophic factor

mBDNF:

mature form of BDNF protein

phosphoTrkB(Y817):

phosphorylated form of TrkB

proBDNF:

immature form of BDNF protein

RNA-seq:

method of massive parallel sequencing

TrkB:

tropomyosin tyrosine kinase receptor B

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Authors and Affiliations

  1. Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russia

    E. A. Rudnitskaya, N. G. Kolosova & N. A. Stefanova

Authors
  1. E. A. Rudnitskaya
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  2. N. G. Kolosova
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  3. N. A. Stefanova
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Correspondence to N. A. Stefanova.

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Original Russian Text © E. A. Rudnitskaya, N. G. Kolosova, N. A. Stefanova, 2017, published in Biokhimiya, 2017, Vol. 82, No. 3, pp. 460-469.

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Rudnitskaya, E.A., Kolosova, N.G. & Stefanova, N.A. Impact of changes in neurotrophic supplementation on development of Alzheimer’s disease-like pathology in OXYS rats. Biochemistry Moscow 82, 318–329 (2017). https://doi.org/10.1134/S0006297917030105

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  • DOI: https://doi.org/10.1134/S0006297917030105

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