Research Papers: Gerotarget (Focus on Aging):
Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats
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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
Nataliya G. Kolosova, e-mail: [email protected]
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
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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