Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats

Natalia A. Stefanova _, Natalia A. Muraleva, Elena E. Korbolina, Elena Kiseleva, Kseniya Yi. Maksimova and Nataliya G. Kolosova

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Oncotarget. 2015; 6:1396-1413. https://doi.org/10.18632/oncotarget.2751

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Abstract

Natalia A. Stefanova1, Natalia A. Muraleva1, Elena E. Korbolina1, Elena Kiseleva1, Kseniya Yi. Maksimova3, Nataliya G. Kolosova1,2,4

1Institute of Cytology and Genetics, Novosibirsk, Russia

2Institute of Mitoengineering, Moscow, Russia

3Siberian State Medical University, Tomsk, Russia

4Novosibirsk State University, Novosibirsk, Russia

Correspondence to:

Nataliya G. Kolosova, e-mail: kolosova@bionet.nsc.ru

Keywords: Alzheimer’s disease, amyloid β, tau, synaptic losses, neurodegeneration, mitochondria, OXYS rats

Received: October 21, 2014     Accepted: November 15, 2014     Published: December 24, 2014

ABSTRACT

The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer’s disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ1–42 and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.


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