Mitochondrial Abnormalities in Alzheimer’s Disease: Possible Targets for Therapeutic Intervention

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Abstract

Mitochondria from persons with Alzheimer’s disease (AD) differ from those of age-matched control subjects. Differences in mitochondrial morphology and function are well documented, and are not brain-limited. Some of these differences are present during all stages of AD, and are even seen in individuals who are without AD symptoms and signs but who have an increased risk of developing AD. This chapter considers the status of mitochondria in AD subjects, the potential basis for AD subject mitochondrial perturbations, and the implications of these perturbations. Data from multiple lines of investigation, including epidemiologic, biochemical, molecular, and cytoplasmic hybrid studies, are reviewed. The possibility that mitochondria could potentially constitute a reasonable AD therapeutic target is discussed, as are several potential mitochondrial medicine treatment strategies.

Introduction

Alzheimer’s disease (AD) is the most prevalent form of dementia. In the United States, it is estimated that one out of every eight persons over the age of 65 suffers from AD, and almost half of those over the age of 85 are affected (Evans et al., 1989; Thies & Bleiler, 2011). It has also been recognized for some time, as Alois Alzheimer’s first reports were presented and published at the start of the twentieth century (Alzheimer, 1907, 1911; Alzheimer et al., 1995). Many academic clinicians and scientists focus on AD, and industry maintains active AD drug development and testing programs.

All this helps create the false impression that we truly understand what AD is, what causes it, and how to effectively treat it. On the contrary, how we even define the disease is somewhat arbitrary, and this really has been the case since the term “Alzheimer’s disease” was first proposed.

By the late nineteenth century, it was recognized that with advancing age, the brain cortex of some animal species develop extracellular protein accumulations called plaques (Blocq & Marinesco, 1892). During the first decade of the twentieth century, this phenomenon was also noted to occur in the brains of elderly humans, and that this histological change was often associated with dementia, a clinical syndrome characterized by declining cognitive function (Fischer, 1907; Redlich, 1898). At this same time, Alois Alzheimer reported the brains of several relatively young, or “presenile,” demented individuals also developed plaque deposits (Alzheimer, 1907, 1911). Alzheimer further described intracellular protein aggregations which he called tangles. Because dementia was relatively common in those reaching old age, affected persons were not felt to have an actual disease, even when plaques and tangles were present (Kraepelin, 1910). Such persons were simply felt to have a senile dementia syndrome that frequently accompanies old age. It was only those with presenile dementia, plaques, and tangles who actually qualified for an AD diagnosis.

Over the next 100 years, much was learned about the structural basis of the plaques and tangles. The major protein in the plaques is folded in an amyloid configuration (Divry, 1927), and is called beta amyloid (Aβ) (Glenner & Wong, 1984). Aβ arises as a degradation product of a larger protein called the amyloid precursor protein (APP) (Kang et al., 1987). The tangles contain aggregated assemblies of a protein called tau, and tau protein in tangles is heavily phosphorylated (Grundke-Iqbal et al., 1986).

During the second half of the twentieth century, the clinical definition underwent significant revision. The distinction between when a demented person with plaques and tangles was young enough to have AD or old enough to have age-associated senile dementia had always been somewhat arbitrary (Swerdlow, 2007a). To minimize the impact of this distinction (Katzman, 1976), the original AD subjects were stated to have presenile dementia of the Alzheimer’s type, while the elderly subjects were said to have senile dementia of the Alzheimer’s type. However, the age boundary between the presenile and senile conditions was still arbitrary, and most reverted to simply calling the clinical syndrome AD, regardless of age.

In the early 1990s, it was shown that mutations in the APP gene, which resides on chromosome 21, cause brain disease in general and can also cause an AD presentation characterized by progressive dementia, plaques, and tangles (Goate et al., 1991; Levy et al., 1990). This discovery gave rise to a hypothesis, the amyloid cascade hypothesis, that posited AD was itself induced by the presence of Aβ-containing amyloid plaques (Hardy & Allsop, 1991).

It was subsequently discovered that mutations in two other genes, the presenilin 1 (PS1) and presenilin 2 (PS2) genes, caused an AD presentation and that the presenilin proteins contributed to APP processing (Kimberly et al., 2000; Levy-Lahad et al., 1995; Sherrington et al., 1995; Wolfe et al., 1999). Aβ was found to be toxic under cell culture conditions (Yankner et al., 1989), and although belief that plaques drove AD neurodysfunction and neurodegeneration gradually fell out of favor, modified versions of the amyloid cascade hypothesis in which different preplaque Aβ configurations were deemed the critical toxic moiety increasingly came to dominate the field (Hardy & Selkoe, 2002; Walsh & Selkoe, 2007). Consistent with this view, transgenic mouse models that developed cortical plaques were created and became the mainstay of preclinical AD research (Hsiao et al., 1996).

Along the way, clinically based AD concepts began to clash with the amyloid cascade hypothesis. The most important discrepancy arose from the fact that plaques are often observed in the brains of the nondemented elderly, a finding not entirely consistent with the idea that Aβ is the primary disease mediator (Swerdlow, 2011a). Recently, this has been administratively addressed by expanding the definition of AD to include anyone with brain plaques, regardless of clinical status. Those with plaques and dementia are now said to have AD, while those with plaques and no clinical signs can be diagnosed with “preclinical AD” (Sperling et al., 2011).

So, despite the fact that many people are diagnosed with it, many investigators study it, and much has been written about it, what we now call AD remains a somewhat arbitrary construct whose definition is subject to change. In essence, the same controversies that were identified over 100 years ago remain. We still do not know whether AD is a single homogeneous entity or a collection of clinically and histologically overlapping conditions. The relationship between brain aging and AD is unclear. Whether Aβ truly induces a disease-driving cascade in all or even some patients remains unproven. To date, a number of therapeutic interventions that benefit AD transgenic mice have been shown not to benefit affected patients, which raises the question of how well these mice model human AD (Holmes et al., 2008; Swerdlow, in press, Swerdlow, 2007a). With this in mind, this chapter will now address the role of mitochondria in AD and the possibility that mitochondria might offer a potential AD therapeutic target.

Section snippets

Mitochondrial Function in AD

AD is usually thought of as a disease of the brain. Biochemical changes, though, are certainly not brain-limited (Swerdlow, 2012). Systemic mitochondrial changes between the mitochondria of AD and age-matched control subjects have been observed.

Mitochondria as a Therapeutic Target in AD

Accumulating data suggest mitochondrial function, if not changes in cell bioenergetics or the pathways that regulate cell bioenergetics, is perturbed early in the course of AD. In this respect, it is possible that at the commencement of AD itself mitochondria are altered by a more upstream process. If so, then treating mitochondrial abnormalities may benefit affected patients to some degree. It may also be the case that mitochondrial or bioenergetic dysfunction may actually constitute the

Conclusion

Many key questions about AD remain unresolved. There is no uniform agreement over whether AD is a homogeneous or a heterogeneous entity, how it relates to brain aging, or even what causes most of the cases. It is clear from a population perspective that mitochondria and mitochondria-related phenomena differ between those who do and do not have this disease. The importance of these mitochondrial and bioenergetic differences to AD, however it is defined, has been variably considered to be

Acknowledgments

The authors receive support from the University of Kansas Alzheimer’s Center (NIA P30AG035982), the Frank and Evangeline Thompson Alzheimer’s Disease Therapeutic Development Fund, and the Portugal Institute of Science and Technology.

Conflict of Interest Statement: The authors have no conflicts of interest to declare.

References (298)

  • D.A. Butterfield et al.

    Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment

    Neuroscience Letters

    (2006)
  • D.A. Butterfield 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 Research

    (2007)
  • T.M. Buttke et al.

    Oxidative stress as a mediator of apoptosis

    Immunology Today

    (1994)
  • M.J. Calkins et al.

    Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons

    Biochimica et Biophysica Acta

    (2011)
  • N.L. Callaway et al.

    Methylene blue improves brain oxidative metabolism and memory retention in rats

    Pharmacology, Biochemistry, and Behavior

    (2004)
  • S.M. Cardoso et al.

    Mitochondrial control of autophagic lysosomal pathway in Alzheimer’s disease

    Experimental Neurology

    (2010)
  • S.M. Cardoso et al.

    Cytochrome c oxidase is decreased in Alzheimer’s disease platelets

    Neurobiology of Aging

    (2004)
  • A.D. Cash et al.

    Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation

    American Journal of Pathology

    (2003)
  • A. Castegna et al.

    Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: Creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1

    Free Radical Biology & Medicine

    (2002)
  • D.C. Chan

    Mitochondria: dynamic organelles in disease, aging, and development

    Cell

    (2006)
  • K. Chandrasekaran et al.

    Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease

    Brain Research. Molecular Brain Research

    (1994)
  • S.W. Chang et al.

    The frequency of point mutations in mitochondrial DNA is elevated in the Alzheimer’s brain

    Biochemical and Biophysical Research Communications

    (2000)
  • H. Chen et al.

    Mitochondrial fusion protects against neurodegeneration in the cerebellum

    Cell

    (2007)
  • G.J. Colurso et al.

    Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer’s disease

    Life Science

    (2003)
  • M. Corral-Debrinski et al.

    Marked changes in mitochondrial DNA deletion levels in Alzheimer brains

    Genomics

    (1994)
  • D.H. Cribbs et al.

    Caspase-mediated degeneration in Alzheimer’s disease

    American Journal of Pathology

    (2004)
  • D. Curti et al.

    Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer’s disease (AD) patients

    Neuroscience Letters

    (1997)
  • J. Dai et al.

    Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes

    Brain Research

    (2002)
  • S.M. de la Monte et al.

    Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer’s disease

    Laboratory Investigation

    (2000)
  • I. Divinski et al.

    A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication

    Journal of Biological Chemistry

    (2004)
  • R.S. Doody et al.

    Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study

    Lancet

    (2008)
  • H. Fukui et al.

    The mitochondrial impairment, oxidative stress and neurodegeneration connection: Reality or just an attractive hypothesis?

    Trends in Neurosciences

    (2008)
  • G.E. Gibson et al.

    Cause and consequence: Mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases

    Biochimica et Biophysica Acta

    (2010)
  • G.G. Glenner et al.

    Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein

    Biochemical and Biophysical Research Communications

    (1984)
  • P.H. Gordon et al.

    Efficacy of minocycline in patients with amyotrophic lateral sclerosis: A phase III randomised trial

    Lancet Neurology

    (2007)
  • M.Y. Aksenov et al.

    The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer’s disease

    Neurochemical Research

    (1999)
  • C.D. Aluise et al.

    Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer’s disease: Insights into memory loss in MCI

    Journal of Alzheimer’s Disease

    (2011)
  • A. Alzheimer

    Uber eine eigenartige Erkrankung der Hirnrinde

    Allgemeine Zeitschrift fur Psychiatrie Psych-Gerichtl Med

    (1907)
  • A. Alzheimer

    Uber eigenartige Krankheitsfalle des spateren Alters

    Zeitschrift für die gesamte Neurologie und Psychiatrie

    (1911)
  • A. Alzheimer et al.

    An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”

    Clinical Anatomy

    (1995)
  • A.J. Anderson et al.

    DNA damage and apoptosis in Alzheimer’s disease: Colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay

    Journal of Neuroscience

    (1996)
  • T.S. Anekonda et al.

    Neuronal protection by sirtuins in Alzheimer’s disease

    Journal of Neurochemistry

    (2006)
  • M.A. Ansari et al.

    Oxidative stress in the progression of Alzheimer disease in the frontal cortex

    Journal of Neuropathology and Experimental Neurology

    (2010)
  • D.M. Arduino et al.

    Mitochondrial fusion/fission, transport and autophagy in Parkinson’s disease: when mitochondria get nasty

    Parkinsons’s Disease

    (2011)
  • H. Atamna et al.

    Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase

    Journal of Alzheimer’s Disease

    (2010)
  • H. Atamna et al.

    Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways

    FASEB Journal

    (2008)
  • J. Avila

    Alzheimer disease: Caspases first

    Nature Reviews. Neurology

    (2010)
  • K. Baar et al.

    Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1

    FASEB Journal

    (2002)
  • S.O. Bachurin et al.

    Mitochondria as a target for neurotoxins and neuroprotective agents

    Annals of the New York Academy of Sciences

    (2003)
  • I. Baldeiras et al.

    Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer’s disease

    Journal of Alzheimer’s Disease

    (2008)
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