Spatial learning as activator of hippocampal neurogenesis during aging and development of Alzheimer\’s disease-like pathology

Poster (download) Alena Burnyasheva1, Tatiana Kozlova2, Ekaterina Rudnitskaya3, Natalia Stefanova41Institute of Cytology and Genetics SB RAS, burnyasheva@bionet.nsc.ru2Institute of Cytology and Genetics SB RAS, kozlova@bionet.nsc.ru3Institute of Cytology and Genetics SB RAS, rudnickaya@bionet.nsc.ru4Institute of Cytology and Genetics SB RAS, stefanovan@bionet.nsc.ru Adult neurogenesis in dentate gyrus (DG) is one of the key mechanisms of neuronal plasticity in hippocampus and plays an important role in cognitive function. However, the consequences of its alteration during healthy aging as well as development of neurodegeneration including Alzheimer’s disease (AD) remain unclear. It was shown that factors which can activate neurogenesis – such as physical exercises and learning – are able to improve cognitive function. Animal models are useful to clarify the connection between adult neurogenesis and cognitive function during development of AD signs, and OXYS rats are a suitable model for the most common sporadic form of AD. Here we examined effects of spatial learning on neurogenesis in DG of OXYS rats prior to and during manifestation of AD signs. We showed altered reference memory of OXYS rats already at the period prior to neurodegeneration. At the period of active manifestation of AD signs OXYS rats demonstrated altered spatial learning and reversal learning, whereas reference memory was altered only a little. At the period of active amyloid-ОІ accumulation in the brain only reference memory of OXYS rats was altered. Spatial learning resulted in accelerated maturation of immature cells of neuronal and astrocytic cell lineages in DG of OXYS and Wistar rats and decrease of amyloid-ОІ content in aged animals.

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MAPK pathways and alphaB-crystallin phosphorylation in brain: a focus on aging and Alzheimer’s disease

Poster (download) Natalia Muraleva11Institute of Cytology and Genetics SB RAS Novosibirsk, Russia, myraleva@bionet.nsc.ru Accumulation of intracellular damage and protein aggregates is an universal hallmark of aging and accompanies the development of some age-related diseases include Alzheimer’s disease (AD). Alpha-B-Crystallin (CryaB) as the molecular chaperone contributes maintenance of proteostasis by prevention of aggregation of proteins (e.g. amyloid beta) and enables their correct refolding. CryaB activity is regulated by MAPK signaling pathway (MAPKsp) through its phosphorylation. Nevertheless, the link between changes in MAPK-dependent CryaB phosphorylation with age and the development of AD remains unclear. Here, we examined p38 MAPK- and ERK-dependent phosphorylation of CryaB in the brain of Wistar rats with normal aging and senescence-accelerated OXYS rats at the different stages of the development of AD-like pathology, including the presymptomatic stage.  The most significant changes identified in the p38 MAPK-dependent CryaB phosphorylation. The level of p-Ser59-CryaB in the brain of Wistar rats increased with the age on the background of p38-MAPKsp activation. Similar but more significant changes accompanied the development of AD-like pathology in OXYS rats. The activation of ERK1/2-dependent CryaB phosphorylation (p-Ser45-CryaB) was detected at the early age and at the late stages of AD-like pathology in OXYS, while changes in the ERK1/2 signaling pathway were detected in Wistar rats with age. Thus, alteration of MAPK-dependent phosphorylation CryaB occurs with the normal aging. Manifestation and progression of the signs of the AD occurs against the background of activation of p38MAPK-dependent phosphorylation of CryaB. Activation of EPK-dependent CryaB phosphorylation is characteristic of the preclinical and progressive stage of the AD-like pathology.

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Effects of melatonin and SkQ1 long-term treatment during aging and development AMD-like retinopathy

Poster (download) Darya V. Telegina1, Oyuna S. Kozhevnikova2, Anzhela Z. Fursova31ICG SB RAS, Novosibirsk, Russia, telegina@bionet.nsc.ru2ICG SB RAS, Novosibirsk, Russia, oidopova@bionet.nsc.ru3ICG SB RAS, Novosibirsk, Russia, anzhellafursova@yandex.ru Melatonin and antioxidant SkQ1 act like mitochondria-targeted antioxidants, which concentrate in mitochondria at relatively high levels and they may prevent mitochondrial damage during retinal aging and development of age-related retinal disease such as age-related macular degeneration (AMD). However, detailed effects of melatonin and SkQ1 on the biochemical mechanisms underlying therapeutic effect of these drugs during retinal aging and AMD progression remain unclear.В  Using Wistar rats with normal aging process and senescence-accelerated OXYS rats, which spontaneously develop a phenotype similar to human age-related disorders including AMD-like retinopathy, we found that treatment of SkQ1 and melatonin decreased the incidence and severity of retinopathy in OXYS rats. In Wistar rats, which do not naturally develop retinopathy, ophthalmoscopic inspections did not reveal pathological alterations in the retina of melatonin and SkQ1-treated rats. SkQ1 decreased p62/SQSTM1 protein but not mRNA levels in both OXYS and Wistar rat\’s retinas as compared of control rats. We observed reduced level of VDAC1 and increased level of glutaminase by long-term treatment of melatonin and SkQ1 in retina of Wistar rats but not OXYS rats. Taken together, our data indicated that long-term treatment of melatonin and mitochondria-targeted antioxidant SkQ1 may retard an age-related decline in the adaptability of retinal cells and may be considered as a strategy to slow down AMD. At the same time effects of melatonin and SkQ1 on molecular events may be different depending on genotype and disease.

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Histological evaluation of postnatal retinal development of senescence-accelerated OXYS rats

Poster (download) Darya V. Telegina1, Anna K. Antonenko2, Oyuna S. Kozhevnikova31ICG SB RAS, Novosibirsk, Russia, telegina@bionet.nsc.ru2NSU, Novosibirsk, Russia, antonenko-98@bk.ru3ICG SB RAS, Novosibirsk, Russia, oidopova@bionet.nsc.ru De novo neurogenesis in the adult mammalian retina very limited. Thereby the structural and functional features formed during the period of maturation and formation of retina can have long-term effects on the further ontogenesis of the tissue, however, the mechanisms of these disorders remain unclear. Using model of premature aging OXYS rats we investigatedВ  the early histopathological changesВ  during postnatal retinal neurogenesis. OXYS rats spontaneously develop a retinopathy similar to age-related macular degeneration (AMD). AMD is a complex neurodegenerative disease resulting in a loss of central vision in the elderly. Ganglion, horizontal, and amacrine cells are born in the embryonic phase of rat developmen. Quantitative analysis showed decreasing amacrine cells in OXYS rats as compared Wistar rats (control). At the age of P0 and P1, the number of ganglion and horizontal cells increased in OXYS rats as compared Wistar rats. Bipolar neurons, photoreceptors and MГјller glia are born postnatally. We did not find changes in Muller cells. The number of photoreceptor\’s nuclei per column in Wistar rats increased at the age of P10 and decreased at the age of P14. In OXYS rats, maximum of number of nuclei per column accounted for age of P14 and then decreased. The number of rod bipolar neurons gradually increased by age of P14 in Wistar rats and P10 in OXYS rats. Our results indicating an alteration of retinal formation in OXYS rats during the postnatal period, which may contribute to the early development of their signs of AMD.

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Mitochondrial dysfunction and redox balance alterations in the development of AD-like pathology in OXYS rats

Poster (download) Mikhail Tyumentsev1, Natalia Muraleva2, Yulia Polienko3, Artyom Gorodetsky4, Elena Bagryanskaya51ICG SB RAS, landselur@bionet.nsc.ru2ICG SB RAS, Myraleva@bionet.nsc.ru3NIOCH SB RAS, polienko@nioch.nsc.ru4NIOCH SB RAS, gorodaa@nioch.nsc.ru5NIOCH SB RAS, egbagryanskaya@nioch.nsc.ru This study focuses on the relationship between mitochondrial dysfunction and redox-status in the context of the development of signs of Alzheimer’s disease (AD). Mitochondrial dysfunction is considered the missing link between brain aging and AD [1], the most common type of age-related dementia worldwide, but the exact causal relationship between mitochondrial dysfunction and the transition from healthy aging to AD remains to be fully understood. Oxidative stress is thought to play a significant role in this mitochondrial dysfunction, leading to cellular damage in redox imbalance. However, the extent of these processes and timing of their occurrence within the scope of AD remain hard to study, especially so in the early, pre-clinical stages of the disease. We explored the mechanisms underlying the disruption of mitochondrial function, their impact on the initiation and progression of pathological molecular cascades of AD, and assessed the changes in redox status as one of the main consequences of oxidative stress. This investigation was conducted using senescence-accelerated OXYS rats, which spontaneously develop all major signs of AD and largely reproduce the stages of the disease. We concluded that mitochondrial dysfunction appears to mediate or possibly even initiate AD-like pathology in OXYS rats. Importantly this takes place with no apparent connection to redox imbalance as on both transcriptional and biochemical levels OXYS rats display no significant changes in redox-status and ROS production as compared to controls.

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Search for single nucleotide polymorphisms (SNPs) associated with hypertension in the genome of senescence-accelerated OXYS rats

Poster (download) Vasiliy A. Devyatkin1, Natalia A. Muraleva2, Olga E. Redina3, Nataliya Kolosova41Institute of Cytology and Genetics SB RAS, devyatkin@bionet.nsc.ru2Institute of Cytology and Genetics SB RAS, myraleva@bionet.nsc.ru3Institute of Cytology and Genetics SB RAS, oredina@bionet.nsc.ru4Institute of Cytology and Genetics SB RAS, Nnnnn80@ngs.ru Aging is a risk factor for many diseases, but the likelihood of developing with age also depends on genetic factors, environmental conditions, lifestyle, and the presence of other pathologies. The OXYS rat strain (ICG SB RAS) is a unique model for studying the mechanisms of aging, as already at an early age these animals develop a whole complex of age-dependent diseases, including cataracts, retinopathy, osteoporosis, hypertension and Alzheimer’s-like pathology. Although hypertension has risk factors typical of age-related diseases, it itself is a risk factor for many other pathologies. However, the complex senile phenotype does not appear in other hypertensive models, even with higher blood pressure. The aim of this study was, based on the results of RNA-Seq, the search for single nucleotide polymorphisms that could contribute to the development of hypertension in OXYS rats with accelerated aging. We found that OXYS rats are genetically far from other strains and presumably have their own bases for the development of hypertension, which may determine the absence of the senile phenotype of OXYS rats in hypertensive rat strains.

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