Regular articleMitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation
Introduction
Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases characterized by declines in memory and cognition. One pathological feature of AD is the presence of abnormal plaques composed of amyloid beta (Aβ) protein deposited in the cortex and hippocampus, regions that are affected in AD.
Mitochondrial dysfunction has been implicated in contributing to the development and progression of AD. Early studies reported defects in oxidative phosphorylation (OXPHOS), specifically cytochrome c oxidase, in postmortem AD brains (Chagnon et al., 1995; Long et al., 2012; Mutisya et al., 1994; Sheng et al., 2012). Mutations in mitochondrial DNA (mtDNA), which encodes proteins for several OXPHOS complexes, have also been found in affected patients (Coskun et al., 2004; Krishnan et al., 2012; Lin et al., 2002). Aging, the major risk factor in developing AD, is associated with declines in mitochondrial function in the central nervous system (Bowling et al., 1993; Hauptmann et al., 2009; Hong et al., 2008; Ross et al., 2010; Yao et al., 2009). Moreover, the cybrid model of AD, in which mtDNA from AD patients' platelets was transferred into cells lacking mtDNA, showed decreased mitochondrial mobility, increased oxidative stress, decreased cytochrome oxidase activity, and decreased mitochondrial membrane potential, suggesting that mitochondria and mtDNA abnormalities contribute to AD pathogenesis (Costa et al., 2012; Swerdlow, 2007).
In support of an alternative hypothesis, in which mitochondrial dysfunction is a consequence rather than a trigger of AD, Aβ negatively affects mitochondrial function. Aβ directly associates with the mitochondria inhibiting OXPHOS (Anandatheerthavarada et al., 2003; Calkins et al., 2011; Casley et al., 2002; Chen and Yan, 2010; Devi et al., 2006; Hansson Petersen et al., 2008; Manczak et al., 2006; Reddy and Beal, 2008). Mitochondrial dynamics are also affected in AD either by the downregulation of fission and/or fusion proteins, or by nitrosylation of dynamin-related protein 1 (DRP1), a mitochondrial fission protein (Manczak et al., 2011; Su et al., 2010; Wang et al., 2009). It is unknown to what extent OXPHOS defects affect and progress the pathophysiology of AD.
Oxidative stress and reactive oxygen species (ROS) damage also contribute to AD pathophysiology. Previous reports showed that ROS enhances β-secretase activity and exacerbates Aβ aggregation (Guglielmotto et al., 2009; Paola et al., 2000; Tamagno et al., 2002; Yao and Brinton, 2012). ROS also influence amyloid precursor protein (APP) processing, promoting Aβ through β- and γ-secretase activation (Leuner et al., 2012a, 2012b; Shen et al., 2008). The electron transport chain is a known source of ROS that can damage proteins, lipids, and DNA. Moreover, some functional alterations in the respiratory chain have been reported to increase ROS production. However, it is unclear whether mitochondria are the sole contributor to the ROS damage seen in AD, because alternative sources of ROS have also been identified (Abramov et al., 2004; Cutler et al., 2004; Yao and Brinton, 2012).
We examined the effect of mtDNA damage on Aβ accumulation and plaque formation to determine how a mild mitochondrial dysfunction affects the pathophysiological changes that occur in a mouse model of AD.
Section snippets
Mice procedures
The generation of Mito-PstI transgenic mice has been previously described (Fukui and Moraes, 2009). The AD transgenic mice, carrying mutant APP and mutant presenilin 1 (The Jackson Laboratory, Bar Harbor, Maine.), were first crossed with CaMKIIα-tTa mice (The Jackson Laboratory). Double-positive mice, AD/CaMKIIα-tTa, were then crossed with Mito-PstI mice to obtain AD/CaMKIIα-tTa/PstI mice that we called “AD-mito-PstI mice”. We called “AD mice” double-positive mice, either AD/CaMKIIα-tTa or
Generation of AD-mito-PstI mice
We previously described the generation and the characteristics of mito-PstI mice using the CaMKIIα promoter (Fukui and Moraes, 2009). Briefly, these mice express a mammalianized version of the bacterial PstI targeted to mitochondria, inserted downstream of a tetracycline response element promoter. Another transgenic allele expresses a tetracycline trans-activator (tTA) gene using the neuronal specific CaMKIIα promoter. When mice harbor both transgenic alleles (PstI+/tTA+), mito-PstI is
Discussion
In this study, we caused mtDNA damage in adult cortical and hippocampal neurons during the period of β-amyloid plaque formation by inducing mito-PstI expression at 6–8 months of age. This is the period when AD mice show marked accumulation of Aβ fragments and amyloid plaques. A 2-month induction period was sufficient to produce a decrease in CoxI content, an mtDNA encoded protein, indicating an mtDNA depletion consequent to PstI induction. We showed that mtDNA damage, which was associated with
Disclosure statement
The authors declare no conflicts of interest.
All experiments and animal husbandry were performed according to a protocol approved by the University of Miami Institutional Animal Care and Use Committee.
Acknowledgements
This work was supported in part by the National Institutes of Health Grants 1R01AG036871, 1R01NS079965, and 5R01EY010804 (CTM), 5T32NS007492, 5T32NS007459, American Heart Association Grant 11Pre7610007, and the Lois Pope LIFE Fellowship (AMP). The authors thank David Jackson (Neuroscience Program) for technical assistance, and Dr Beata Frydel and the Lois Pope LIFE Center Histology Core for the access and use of their microtome, reagents, and light microscopes.
References (71)
- et al.
Generation of amyloid beta protein from its precursor is sequence specific
Neuron
(1995) - et al.
Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer's disease
Life Sci.
(2003) - et al.
Amyloid beta-induced ER stress is enhanced under mitochondrial dysfunction conditions
Neurobiol. Aging
(2012) - et al.
The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway
Neurobiol. Dis.
(2008) - et al.
Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
Neurobiol. Dis.
(2006) - et al.
Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice
Neurobiol. Aging
(2009) - et al.
Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease
Neurobiol. Aging
(2012) - et al.
Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes
J. Neurol. Sci.
(2007) - et al.
Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells
Biochem. Biophys. Res. Commun.
(2000) - et al.
Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease
Trends Mol. Med.
(2008)
Proteolysis of A beta peptide from Alzheimer disease brain by gelatinase A
Biochem. Biophys. Res. Commun.
Behavioral stress causes mitochondrial dysfunction via ABAD up-regulation and aggravates plaque pathology in the brain of a mouse model of Alzheimer disease
Free Radic. Biol. Med.
Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase
J. Biol. Chem.
Oxidative stress increases expression and activity of BACE in NT2 neurons
Neurobiol. Dis.
Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer's disease
Neurobiol. Aging
Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease
Adv. Pharmacol.
Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase
J. Neurosci.
Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells
J. Cell Biol.
Upregulated function of mitochondria-associated ER membranes in Alzheimer disease
EMBO J.
Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40)
J. Neurosci.
Age-dependent impairment of mitochondrial function in primate brain
J. Neurochem.
Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease
Hum. Mol. Genet.
Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities
J. Neurochem.
Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases
Neuroreport
Role of mitochondrial amyloid-beta in Alzheimer's disease
J. Alzheimers Dis.
Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication
Proc. Natl. Acad. Sci. U.S.A
ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria
J. Alzheimers Dis.
Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease
Proc. Natl. Acad. Sci. U.S.A
Mitofusin 2 tethers endoplasmic reticulum to mitochondria
Nature
Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction
J. Neurosci.
Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease
Proc. Natl. Acad. Sci. U.S.A
Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons
Hum. Mol. Genet.
Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures
Arch. Neurol.
Oxidative stress and hypoxia contribute to Alzheimer's disease pathogenesis: two sides of the same coin
ScientificWorldJournal
The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
Proc. Natl. Acad. Sci. U.S.A
Cited by (0)
- 1
Contributed equally to this work.
- 2
Present address: Surgical Neurology Branch, NINDS/National Institutes of Health Bethesda, MD, USA.