Intraneuronal amyloid β accumulation and oxidative damage to nucleic acids in Alzheimer disease
Introduction
Amyloid plaques, filamentous deposits of the amyloid-β (Aβ) peptide in the extracellular space, are defining lesions in Alzheimer disease (AD) brain. The accumulation of Aβ has been demonstrated to occur within neurons prior to extraneuronal deposition of Aβ plaques in patients with Down syndrome, an example of Alzheimer-type neurodegeneration (Gyure et al., 2001, Mori et al., 2002), and in transgenic mouse models of AD (Wirths et al., 2001, Oddo et al., 2003, Lord et al., 2006, Oakley et al., 2006). In AD, intraneuronal Aβ accumulation is evident at early-stages of the disease, including a prodromal stage characterized by mild cognitive impairment (MCI), and subsequently tends to decrease with the emergence of more prominent extraneuronal plaque pathology (Gouras et al., 2000, Gouras et al., 2005). Thus, intraneuronal Aβ accumulation is a significant early-stage event in AD.
In contrast, oxidative stress and oxidative cellular damage have been reported to be one of the earliest events in vulnerable neurons of AD (Nunomura et al., 2001, Nunomura et al., 2006, Nunomura et al., 2009). Indeed, oxidative damage can be detected prior to the extraneuronal deposition of Aβ plaques in patients with Down syndrome (Nunomura et al., 2000) and in transgenic mice or knock-in mouse models of AD (Praticò et al., 2001, Anantharaman et al., 2006, Resende et al., 2008). In AD and Down syndrome, oxidative damage is more prominent in patients with shorter disease duration and with lesser amount of extraneuronal deposition of Aβ (Cuajungco et al., 2000, Nunomura et al., 2000, Nunomura et al., 2001, Nunomura et al., 2004), and is present in brains of subjects with MCI (Ding et al., 2005, Keller et al., 2005, Markesbery et al., 2005, Butterfield et al., 2006, Butterfield et al., 2007, Wang et al., 2006, Lovell and Markesbery, 2008). Correspondingly, oxidative damage is a significantly early event in AD that is potentially correlated to the intraneuronal Aβ accumulation that characterizes the disease.
Experimentally, Aβ can be used to induce oxidative stress (Behl et al., 1994, Hensley et al., 1994, Schubert et al., 1995, Mark et al., 1997, Tabner et al., 2005), and, on the other hand, oxidative stress can induce Aβ production and accumulation (Yan et al., 1995, Frederikse et al., 1996, Paola et al., 2000, Misonou et al., 2000, Tong et al., 2005, Tamagno et al., 2005, Tamagno et al., 2008, Shen et al., 2008). However, whether Aβ accumulation is primary to oxidative stress or oxidative stress is primary to Aβ accumulation is yet undetermined in AD. In this study, we investigated the distribution of and relationship between the levels of intraneuronal Aβ accumulation and oxidative damage to nucleic acids in AD brains. We focused on nucleic acid oxidation because of its pathogenic significance in neurodegeneration (Nunomura et al., 1999, Nunomura et al., 2001, Nunomura et al., 2004, Nunomura et al., 2006, Zhang et al., 1999, Klein et al., 2002, Shan et al., 2003, Shan et al., 2007, Shan and Lin, 2006, Chang et al., 2008) and its utility as a sensitive “steady-state” marker of oxidative stress (Nunomura et al., 2007, Nunomura et al., 2009) that reveal the chronological relationship between intraneuronal Aβ accumulation and oxidative damage. Altogether, we found more widespread distribution of neuronal oxidative damage compared with intraneuronal Aβ accumulation as well as an inverse relationship between them suggesting a possible scenario in which intraneuronal oxidative stress may elicit Aβ in AD as a compensatory measure.
Section snippets
Tissue
Brain tissue was obtained at autopsy from 16 clinically and pathologically confirmed cases of AD (5 males and 11 females; ages 65–93 years, average 81) according to the National Institute on Aging (NIA) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria (Khachaturian, 1985, Mirra et al., 1991). Postmortem intervals prior to fixation were 3–37 h (average 8 h). Hippocampal slices (∼ 1 cm thick and including the surrounding subiculum, and entorhinal cortex) were
Results
An in situ approach with antibodies specific to the carboxyl terminus of Aβ42 revealed an accumulation of intraneuronal Aβ42 with moderate to strong immunoreactivities in brain tissue of the hippocampus and the subiculum from subjects with AD. This intraneuronal Aβ42 immunoreaction was especially evident within pyramidal neurons and showed a distinct granular pattern in the perikaryal cytoplasm (Fig. 1A). Compared with the intraneuronal Aβ42 immunoreactivity, relatively little Aβ40
Discussion
As previously shown in postmortem brains of AD and Down syndrome, as well as in the brains of transgenic animal models of AD, we observed neuron-associated Aβ42 accumulation and nucleic acids oxidation inside the cell soma in vulnerable regions of AD brains. It is possible that the intraneuronal Aβ has a causal role in neuronal oxidative damage because higher concentrations of Aβ, in the micromolar range, can lead to oxidative stress in various biological systems (Behl et al., 1994, Hensley et
Conclusion
An inverse relationship between intraneuronal immunoreactivities of Aβ42 and nucleic acid oxidation has been shown in the hippocampus of AD brains. Intraneuronal accumulation of Aβ42 may be involved in a protective cellular mechanism to cope with oxidative insults in AD. Further investigations are required to understand the assembly state-dependent properties of Aβ and their roles in redox pathophysiology in AD.
Acknowledgments
Work in the authors' laboratories is supported by funding from the Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research (C) 20591387 to AN), the National Institutes of Health (R01 AG026151 to MAS), and the Alzheimer's Association (ZEN-07-59500 to GP).
References (82)
- et al.
β-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH × PS-1P264L/P264L double knock-in mouse model of Alzheimer's disease
Am. J. Pathol
(2006) - et al.
Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β
Brain Res. Brain Res. Rev.
(2003) - et al.
Hydrogen peroxide mediates amyloid β protein toxicity
Cell
(1994) - et al.
Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease
Neurobiol. Dis.
(2006) - et al.
Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease
Brain Res.
(2007) - et al.
Evidence that the β-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of Aβ by zinc
J. Biol. Chem.
(2000) - et al.
Aβ oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
J. Biol. Chem.
(2007) - et al.
Oxidative stress increases production of β-amyloid precursor protein and β-amyloid (Aβ) in mammalian lenses, and Aβ has toxic effects on lens epithelial cells
J. Biol. Chem.
(1996) - et al.
Intraneuronal Aβ accumulation and origin of plaques in Alzheimer's disease
Neurobiol. Aging
(2005) - et al.
Intraneuronal Aβ42 accumulation in human brain
Am. J. Pathol.
(2000)