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

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.

An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology

“…In line with their hippocampus-dependent cognitive deficits, OXYS rats show a synaptic loss [31], prominent alterations of synaptic functions [33], and significant ultrastructural changes [28] in the hippocampus. Ultrastructural abnormalities in synaptic terminals of OXYS rats in the period of progression of AD-like pathology are characterized by decreased numbers of synaptic vesicles, by signs of their disorganization and destruction, by increased numbers of various vacuoles, and by swelling and disintegration of mitochondria [31].…”

“…Because progressive accumulation of toxic amyloid-β species in the brain of OXYS rats starts at age 12 months [27–28], we tested whether treatment with SkQ1 since 12 months of age affects amyloid-β 1-40 and amyloid-β 1-42 levels in the hippocampus of 18-month-old OXYS rats. Enzyme immunoassay analysis of amyloid-β 1-40 and amyloid-β 1-42 (Fig.…”

“…Because the levels of tau protein and of its phosphorylated form are increased in the brain of OXYS rats already at age 3 months [28], we then evaluated the ability of SkQ1 to slow down the hyperphosphorylation of tau protein in the hippocampus during progression of AD-like pathology. Western blot analysis of Tau and of its phosphorylated forms pT181, pS262, and pS396 (Fig.…”

“…Recently, we showed that OXYS rats simulate key characteristics of the sporadic form of AD [25–27]. More recently, we reported that an age-dependent increase in the levels of amyloid-β 1–42 and extracellular amyloid-β deposits in the brain of OXYS rats occur later than do mitochondrial structural abnormalities, hyperphosphorylation of the tau protein, synaptic loss, and neuronal cell death [28]. On the basis of our results, we theorized that multiple age-associated degenerative processes may precede the toxic accumulation of amyloid-β, which in turn triggers the final, currently irreversible stage of AD.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…18,19 Recent support for the amyloid hypothesis of AD came from a study which recapitulated the disease in a 3D human neuronal cell culture model, demonstrating that the appearance of prominent neurofibrillary tangles requires Ab generation, 20 a causality that is still controversial. 21 While APP triplication in trisomy 21 and mutations in APP and PSEN1 or PSEN2 of the g-secretase complex are known to engender familial AD, contributions of BACE1 polymorphisms remain to be established. 22 Nevertheless, the importance of BACE1 in AD pathogenesis has been demonstrated by mutations in APP, which either promote b-site cleavage causing a familial form of early-onset AD, or, contrarily, hinder APP b-cleavage and thus protect against the disease and even mild cognitive impairment.…”