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ROLE OF MITOCHONDRIA IN NEURODEGENERATIVE

r DISEASES: MITOCHONDRIA AS A THERAPEUTIC
TARGET IN ALZHEIMER'S DISEASE
P. Hema chandra Reddy, PhD

Introduction Importance of Mitochondria in

A growing body of evidence suggests that mitochon- Neurodegenerative Diseases
drial abnormalities are involved in aging and in age-related Mitochondria are cytoplasmic organelles essential for
neurodegenerative diseases as well as cancer, diabe- life and death. They perform several cellular functions
tes, and several other diseases known to be affected including: intracellular calcium regulation; adenosine tri-
by mitochondria.13 Causal factors for most age-related phosphate (ATP) production; the release of proteins
neurodegenerative diseases—including Alzheimer's dis- that activate the caspase family of proteases; alteration
ease, Parkinson's disease, amyotrophic lateral sclerosis of the reduction-oxidation potential of cells; and free-
(ALS), and Friedrich ataxia (FRDA)—are largely unknown. radical scavenging.8 Mitochondria are compartmental-
Genetic defects are reported to cause a small number of ized into two lipid membranes: the outer mitochondrial
neurodegenerative diseases (Slide 1), but cellular, molec- membrane and the inner mitochondrial membrane. The
ular, and pathological mechanisms of disease progression outer membrane is porous and allows the passage of
and selective neuronal cell death are not understood low molecular-weight substances between the cytosol
fully in these diseases. However, based on several cel- and the inter-membrane space. The inner membrane
lular, molecular, and animal model studies of Alzheimer's provides a highly efficient barrier to ionic flow, houses
the mitochondrial respiratory chain or electron transport
disease, Parkinson's disease, ALS, FRDA, cancer, and
chain (ETC), and covers the mitochondrial matrix, which
diabetes, aging may play a large role in cell death in these
contains tricarboxylic acid (TCA) and beta-oxidation (Slide
diseases.46 Age-dependent, mitochondrially-generated
2). Mitochondria are transmitted maternally. However, in
reactive oxygen species (ROS) have been identified as
rare situations, paternal inheritance and a recombination
important factors responsible for disease progression of mitochondrial DNA (mtDNA) have been reported.7
and cell death, particularly in late-onset diseases, in Mitochondria are controlled by both nuclear and mito-
which genetic mutations are not causal factors. 12A6J chondrial genomes. mtDNA consists of a 16,571 base-pair,
This article discusses the role of mitochondria in the double-stranded, circular DNA molecule.9 A mitochon-
progression of age-related neurodegenerative diseases, drion contains 2-10 copies of mtDNA.2 mtDNA contains
the connection between mitochondrial abnormalities and 13 polypeptide genes that encode essential components
Alzheimer's disease progression, and medications tar- of the ETC. mtDNA also encodes the 12S and 16S rRNA
geted to mitochondria in Alzheimer's disease along with genes and the 22 tRNA genes required for mitochondrial
other neurodegenerative diseases. protein synthesis.10 Nuclear genes encode the remaining

Dr. Reddy is a scientist in the Division of Neuroscience at the Oregon National Primate Research Center in Beaverton.
Disclosures: Dr. Reddy reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Reddy discusses unap-
proved/experimental uses of dimebon in the treatment of Alzheimer's disease.
Acknowledgements: The research presented in this article was supported by grants from American Federation for Aging Research and the National
Institutes of Health (AG020872 and AG025061).
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proteins, metabolic enzymes, DNA and RNA polymerases, In the respiratory chain, complexes I and III leak electrons
ribosomal proteins, and mtDNA regulatory factors, such as to oxygen, producing primarily superoxide radicals. The
mitochondrial transcription factor A. Nuclear-encoded mito- superoxide radicals are dismutated by manganese super-
chondrial proteins are synthesized in the cytoplasm and are oxide dismutase (Mn-SOD), generating H2O2 and oxygen.
Complex I generates only toward the mitochondrial matrix,
subsequently transported into mitochondria.
but complex III generates toward both the inter-membrane
space and the matrix. In addition, the components of tricar-
Sites of Free Radical Production in the boxylic acid cycle, including a-ketoglutarate dehydrogenase,
generate superoxide radicals in the matrix. These mitochon-
Mitochondria
drially-generated free radicals and superoxide radicals are
Mitochondrial ATP is generated via oxidative phosohoryla- carried to the cytoplasm via voltage-dependent anion chan-
tion (OXPHOS) within the inner mitochondrial membrane. nels and participate in lipid peroxidation, and protein and
Free radicals are generated as a byproduct of OXPHOS. DNA oxidation. Mitochondria are critical in the metabolism

SLIDE 1
Common, Age-Related Diseases That Involve Mitochondrial Abnormalities

Age-Related
Diseases Prevalence Mitochondrial Abnormalities
Aging Aging is critical in several diseases DNA defects in the mitochondrial genome are responsible for aging and
that involve mitochondrial dysfunction. senescence. Accumulation of DNA defects is responsible for increased
ROS production and oxidative damage in aged tissues.

Cancer Most common in the aged Tumor cells excessively accumulate mitochondrial DNA defects and
(a60 years of age) decrease mitochondrial respiration and ATP synthesis. Cancer cells up-
regulate enzymes of glycolysis and adapt to decreased oxygen tension,
a characteristic of most solid tumors.
Worldwide, 8% of the population suf- Hyperglycemia causes pathological features of type 1 and 2 diabetes.
fers from diabetes. Increased free radical production is found in hyperglycemia and has
been found to disrupt glucose-stimulated insulin secretion by pan-
creatic p cells.
Worldwide, 5% of people a65 years Amyloid precursor proteins and Ap are found in mitochondrial mem-
of age and 50% of people a85 years branes and in the matrix of neurons affected by AD. Mitochondria APP
of age suffer from AD. Of the total and Ap induce free radicals, decrease cytochrome oxidase activity,
number of AD patients, 2% have and inhibit ATP production.
genetic mutations in APP, PS1, and N-terminal ApoE4 is associated with mitochondria and causes mitochon-
PS2 genes. drial oxidative damage.
Worldwide, 0.5% to 1% of people 65- Both wild-type and mutant a-syWtarein a r t f t S M tn the mitochondrial
69 years of age suffer from PD. membranes and are determined to cause mitochondrial dysfunction.
DJ1 is a redox sensor protein, localized to mitochondrial inter-membrane
space and matrix. PINK1 is a nuclear-encoded, mitochondrial kinase
protein. Overexpression of PINK1 causes reduced mitochondrial mem-
brane potential. Parkin is a gene product of Ubiquitin E3 ligase and is
associated with the outer mitochondrial membrane. Parkin induces free
radical production. LRRK2 is associated with the outer mitochondrial
membrane and may induce free radicals. 0MI/HTRA2 is a pro-apoptotic
serine protease found in the mitochondrial inter-membrane space.

Four to 10 people per 100,000 (mostly Mutant huntingtin binds to the outer mitochondrial membrane and induces
Caucasian people) suffer from HD. free radical production. This induction is interrupted with calcium uptake.
Mitochondrial movement is interrupted in mitochondria from HD neurons.

One to two people per 100,000 (variety SOD1 is a cytosolic ROS scavenging enzyme. Mutant S0D1 aggregates
of ethnic groups) suffer from ALS; 10% have been found in the outer mitochondrial membrane, the inner mito-
of the total number of ALS patients chondrial membrane space, and the matrix. Mutant S0D1 induces free
have genetic defects. radicals and mitochondrial dysfunction in ALS patients.

Worldwide, 1-2 persons per 100,000 Frataxin, the gene product of Friedreich ataxia, is a mitochondrial protein
(variety of ethnic groups) that is responsible for heme biosynthesis and the formation of iron-sulfur
clusters. Mutations in frataxin facilitate the accumulation of iron in mito-
chondria, induce free radicals, and cause mitochondrial dysfunction.
ROS=reactive oxygen species; ATP=adenosine triphosphate; AD=Alzheimer's disease; Ap=amyloid beta; APP=amyloid precursor protein; PS=presenilin;
ApoE4=apolipoprotein E; PD=Parkinson's disease; DJ1=PARK7 {Parkinson disease protein 7); PINK=phosphatase and tensin homolog (PTENI-induced puta-
tive kinase 1; LRRK2=leucine-rich repeat kinase 2; OMI/HTRA=HtrA serine peptidase localized to mitochondrial intermembrane space; HD=Huntington's disease;
ALS=amyotrophic lateral sclerosis; SOD=superoxide dismutase.

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of all mammalian cells, including brain neurons, and abnor- progression, which is why late-onset Alzheimer's disease
malities in mitochondrial structure and function may lead to and Parkinson's disease patients take more time to exhibit
age-related neurodegenerative diseases. pathological features. Age-related mitochondrial abnor-
malities contribute to disease progression in late-onset
Alzheimer's disease and Parkinson's disease. However,
Mutant Proteins Associated with if age-dependent mitochondrial abnormalities are likely
Mitochondria factors affecting the development of Alzheimer's disease
and Parkinson's disease (and possibly even affecting can-
Several recent molecular, cellular, biochemical, and
cer and diabetes in aged patients), it is still unclear what
animal model studies of inherited neurodegenerative
makes some aged patients susceptible to Parkinson's
diseases revealed that mutant proteins—such as amy- disease development and others, to Alzheimer's disease.
loid beta (Ap) in Alzheimer's disease, mutant huntingtin Epigenetic factors and lifestyle activities may contribute to
in Huntington's disease (HD), mutant SOD1 in ALS, age-dependent susceptibility to these diseases.
mutant parkin, mutant DJ1, and mutant a-synuclein in
In HD, mutant huntingtin, in association with outer mito-
Parkinson's disease, and frataxin in FRDA—are localized
chondrial membrane, may block mitochondrial pores and dis-
to mitochondrial membranes, leading to an increased pro-
rupt the transport of nuclear-encoded mitochondrial proteins
duction of free radicals, a low production of cellular ATP, to mitochondria and may induce free radical production and
and ultimately cell death (Slide 3). 24 Increasing evidence calcium influx. These events occur more frequently in neu-
suggests that mitochondrial dysfunction is a common rons affected by HD than in neurons unaffected by HD.11
cellular change in the disease progression of several neu-
rodegenerative diseases, cancer, and diabetes.
Alzheimer's Disease and Mitochondrial
Role of Aging and Epigenetic Factors in Dysfunction
Neurodegenerative Diseases Alzheimer's disease is a late-onset, progressive, age-
dependent neurodegenerative disease, characterized by
In Alzheimer's disease and Parkinson's disease, there the progressive decline of memory, cognitive functions,
are no differences pathologically between early onset and changes in behavior and personality.71213 Two major
familial patients and late onset patients. The only differ- pathological features have been observed in postmortem
ence is that in late-onset patients, pathological changes brains from Alzheimer's disease patients: intracellular
occur later than in the early-onset patients. In early-onset
cases, genetic mutations accelerate the disease pro-
cess. In late-onset patients, in the absence of genetic SLIDE 3
mutations, age-related cellular changes control disease Mutant Proteins and Mitochondria2-4

SLIDE 2
Structure of Mitochondria

In AD, Ap peptides enter mitochondria and interact with mitochondrial proteins,

induce free radicals, decrease cytochrome oxidase activity, and inhibit ATP genera-
liner membrane ipace
tion. In brains of AD patients, APP is transported to outer mitochondrial membranes,
blocks the import of nuclear cytochrome oxidase proteins to mitochondria, and may
be responsible for decreased cytochrome oxidase activity. In HD neurons, mutant Htt
A mitochondrion is compartmentalized with two lipid membranes: the inner mitochon- binds to the outer mitochondrial membrane and induces free radical production. Free
drial membrane and the outer mitochondrial membrane. The inner mitochondrial mem- radicals may interrupt with calcium uptake. In PD neurons, mutant proteins of a-synu-
brane houses the mitochondrial respiratory chain and provides a highly efficient barrier clein, parkin, PINK1, and DJ1 are associated with mitochondria and cause mitochon-
to ionic flow. In the ETC, complexes I and III leak electrons to oxygen, producing primar- drial dysfunction. Complex I activity is inhibited in PD neurons. In ALS, mutant S0D1
ily superoxide radicals. Superoxide radicals are dismutated by manganese superoxide is localized to the inner and outer mitochondrial membranes and matrix, and induces
dismutase and produce H202. In addition, ETC involves H2O2 reducing to H20 and 02 by free radical production and oxidative damage. Impairment of complexes II and IV are
catalase or glutathione peroxidase accepting electrons donated by NADH and FADH2 associated with ALS. Frataxin is a mitochondrial protein responsible for heme biosyn-
and then yielding energy to generate ATP from adenosine diphosphate and inor- thesis and the formation of iron-sulfur clusters. In Friedriech ataxia, mutant frataxin
ganic phosphate. Free radicals are also generated by tricarboxylic acid in the matrix. facilitates the accumulation of iron in mitochondria and induces free radicals.

DNA=deoxyribonucleic acid; ALS=amyotrophic lateral sclerosis;

MtDNA=mitochondrial deoxyribonucleic acid; VDAC=voltage dependent anion ApoE4=apolipoprotein E; APP=amyloid precursor protein; SOD=superoxide dis-
channel; Ca++=intracellular calcium; H202=hydrogen peroxide; ANT=adenine mutase; Ab=amyloid beta; CyPD=cyclophilin D; ABAD=amyloid binding alcohol
nucleotidetranslocase; 02*-=superoxide radical;TCA=tricarboxylic acid; IM=inner dehydrogenase; TCA=tricarboxylic acid; 0MI/HTRA=HtrA serine peptidase local-
membrane; MnSOD=manganese superoxide dismutase; GPx=glutathione peroxi- ized to mitochondrial intermembrane space; LRRK2=leucine-rich repeat kinase
dase; 0M=outer membrane; ADP=adenosine diphosphate; Pi=inorganic phosphate; 2; P!NK=phosphatase and tensin homolog (PTENHnduced putative kinase 1;
ATP=adenosine triphosphate; ETC=electron transport chain; NADH=reduced nico- DJ1=PARK7 (Parkinson disease protein 7); Htt=huntingtin; AD=Alzheimer's disease;
tinamide adenine dinucleotide; FADH=reduced flavin adenine dinucleotide. ATP=adenosine triphosphate; HD=Huntington's disease; PD=Parkinson's disease.

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gles and extracellular AB deposits in the regions of the brain and in Alzheimer's disease patients. In addition, mitochon-
that are responsible for learning and memory. Alzheimer's drial trafficking is largely interrupted in neurons affected by
disease is also associated with the loss of synapses, syn- Alzheimer's disease. In normal, healthy neurons, mitochondria
aptic function, mitochondrial abnormalities, inflammatory move from cell body to axons, dendrites, and synapses by an
responses, and neuronal loss. Genetic mutations in APR PS1, anterograde mechanism, supplying ATP at nerve terminals.
and PS2 genes cause - 2 % of all Alzheimer's disease cases; Mitochondria then travel back to the cell body from synapses
however, causal factors are still unknown for a vast majority through a retrograde mechanism. In Alzheimer's disease neu-
of Alzheimer's disease patients. Several factors—including rons, these mechanisms are abnormal primarily due to defec-
lifestyle, diet, environmental exposure, apolipoprotein allele tive or functionally inactive mitochondria (Slide 4).17 Recently,
E4, and a genetic variant in sortilin-related receptor 1 gene mitochondrial abnormalities have been identified: changes in
(SORL1)—may contribute to late-onset Alzheimer's disease.7 mitochondrial DNA; decreased mitochondrial enzyme activi-
Genetic mutations in APP, PS1, and PS2 genes are reported ties; abnormal mitochondrial gene expressions; increased
to accelerate cellular changes in Alzheimer's disease patho- mitochondrial fragmentation; and decreased mitochondrial
genesis, including AB production and formation of AB depos- fusion.17 These events occur very early in the development
its, and accumulation of AB in subcellular organelles, such as and progression of Alzheimer's disease.
mitochondria, endoplasmic reticulum, and lysosomes. This
abnormal AB accumulation impairs the functions of subcellular
organelles in Alzheimer's disease neurons.7 Mutant APP and A(3 Associated with
Alzheimer's disease prevalence is high among aged Mitochondria
people: 5% of patients 65 years of age and 50% of Several lines of evidence from studies of neurons
patients a85 years of age.14 These numbers translate to in postmortem brain specimens from patients with
extremely high health care costs. Alzheimer's disease patients and from Alzheimer's dis-
Although Alzheimer's disease pathogenesis involves a ease mice suggest that APP derivatives, including AB
large number of molecular and cellular events, two events monomers and oligomers, are associated with mitochon-
that occur early in Alzheimer's disease development are drial membranes.18"21 Recently studies also found that AB
synaptic damage and mitochondrial dysfunction.71516 These is transported into mitochondria via the translocase of the
two events are likely caused by mutant APP/AB and aging. It outer membrane machinery.22
is generally accepted that an age-dependent accumulation of Several recent in vitro and in vivo studies found APP
AB at synapses and synaptic mitochondria interfere with syn- in mitochondrial membranes, in neurons affected by
aptic activities, including the release of synaptic vesicles and Alzheimer's disease.212326 Interestingly, these studies also
neurotransmitters, and the production of ATP at synapses. For found that APP is localized to the mitochondria, N-terminal
normal communication across neurons, and normal cognitive part of the protein inside the mitochondria and thre C-termi-
and memory functions, it is critical that synaptic activities and nal of the protein that faces outside the mitochondria.2326
ATP supply are normal. However, it is these events that are Devi and colleagues21 found that full-length APP and C-ter-
interrupted with increasing frequency in elderly individuals minal truncated (lacking AB domain) APP species accumulate
in mitochondria, in patients with mild, moderate, and severe
Alzheimer's disease, but not in the age-matched healthy sub-
SLIDE 4 jects.21 They also found that APP increasingly accumulate in
Abnormal Mitochondrial Movements in AD Neurons'7
mitochondrial membranes as Alzheimer's disease progress-
Healthy Neuron Alzheimer's Disease Neuron es, suggesting that APP is associated with mitochondria and
is critically involved in Alzheimer's disease progression.

Mitochondrial Abnormalities in Alzheimer's

Disease
Mitochondrial dysfunction has been observed in
Alzheimer's disease postmortem brains, in platelets from
Alzheimer's disease patients, in Alzheimer's disease
transgenic mice, and in cell lines that express mutant
APP and/or cells treated with AB.17 Several lines of evi-
dence suggest that mitochondrial abnormalities play a
large role in Alzheimer's disease pathogenesis.

Abnormal Mitochondrial Enzyme Activities

In healthy neurons, mitochondria move from cell body to axons, dendrites, and syn-
apses by an anterograde mechanism, supplying ATP at nerve terminals. Mitochondria Studies of mitochondrial enzyme activities found
then travel back to the cell body from synapses through a retrograde mechanism. In decreased levels of cytochrome oxidase activity, pyruvate
AD neurons, these mechanisms are abnormal primarily due to defective or functionally
inactive mitochondria. Mitochondria associated with mutant APP and Ap are largely
dehydrogenase, and a-ketodehydrogenase in fibroblasts,
dysfunctional and not able to move from cell body to synapses and supply ATP to nerve lymphoblasts, and postmortem brains from Alzheimer's
terminals (shown in red). Decreased ATP levels at synapses contribute to synaptic disease patients, compared to neurons, fibroblasts,
degeneration, synaptic loss and ultimate neuronal death and cognitive impairments.
and lymphoblasts from age-matched healthy subjects.7
AD=Alzheimer's disease; ATP=adenosine triphosphate; APP=amyloid pre- Furthermore, deceased mitochondrial enzyme activities
cursor protein; A^-amyloid beta. were found in the affected regions of brain in transgenic
mouse models of Alzheimer's disease.1820
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Defective Mitochondrial Function mixed results. Some epidemiologic studies suggest that
the increased intake of antioxidant vitamins (including vita-
Several studies found increased free radical production, min E, vitamin C, and beta carotene) may reduce the risk
lipid peroxidation, oxidative DNA damage, oxidative protein of developing Alzheimer's disease or Parkinson's disease,
damage, decreased ATP production, and decreased cell via- while other studies did not.7 Currently, available antioxidant
bility in postmortem Alzheimer's disease brains (particularly approaches are not effective in treating neurodegenerative
in the affected regions such as hippocampus and cortex but diseases because naturally occurring antioxidants, such as
not in the unaffected region such as cerebellum) compared vitamins E and C, do not cross the blood-brain barrier and
to brains from age-matched healthy subjects.2126"29 cannot reach the relevant sites of free radical generation.
To overcome these problems and to better assess whether
Mitochondrial DNA Defects antioxidant approaches may be valuable therapeutic treat-
ments, improved delivery of antioxidants to the brains of
Mitochondrial DNA changes were increased in postmor- patients with neurodegenerative diseases is needed.
tem brain tissue from patients with Alzheimer's disease and
In the last decade, considerable progress has been
aged-matched healthy subjects, compared to DNA changes
made in developing mitochondrially targeted antioxidants.
in postmortem brain tissue from young, healthy subjects,
To increase the delivery of antioxidants into mitochondria,
suggesting that the accumulation of mitochondrial DNA in
several agents have been developed: the triphenylphospho-
Alzheimer's disease pathogenesis is age-related.3031
nium-based antioxidants (MitoQ, MitoVitE, and MitoPBN),
the cell-permeable, small peptide-based antioxidant SS31,
Abnormal Mitochondrial Gene Expression and mitochondrial permeability transition pore inhibitors,
such as dimebon.2'38"40 The application of these mitochondri-
Several groups investigated mitochondrial gene expres-
ally targeted agents to neurodegenerative diseases is at its
sions in postmortem Alzheimer's disease brains and in brain
early stages and is focused on animal models of Alzheimer's
specimens from Alzheimer's disease transgenic mice.32"34
disease, Parkinson's disease, and ALS. One recent clinical
They found mitochondrially encoded genes abnormally
study of dimebon showed significant improvement in the
expressed in the brains of patients with Alzheimer's disease
clinical course of mild-to-moderate Alzheimer's disease as
and Alzheimer's disease mice. A recent, time-course global
well as evidence that it was safe and well-tolerated.40
gene expression study in Tg2576 mice and age-matched
non-transgenic littermates revealed an up-regulation of mito- Recently, Wu and colleagues41 found that dimebon acts
chondrial genes in the Tg2576 mice, suggesting that mito- as an inhibitor of N-methyl-D-aspartic acid (NMDA) receptors
chondrial metabolism is impaired by mutant APP/Ap and that and voltage-gated calcium channels in neurons from wild-
the up-regulation of mitochondrial genes may be a compen- type mice and in HD YAC128 transgenic mice. They also
satory response to mutant APP/Ap.33 Further, Manczak and found that dimebon 50 uM stabilized glutamate-induced Ca2+
colleagues34 found an abnormal expression of mitochondrial- signals in aYAC128 medium of spiny neurons and protected
ly encoded genes in postmortem Alzheimer's disease brains the neurons from glutamate-induced apoptosis. Findings
compared to the brains of healthy subjects,34 suggesting from this study suggest that dimebon may beneficially
impaired mitochondrial metabolism in Alzheimer's disease. affect HD neurons through its capacity to alter NMDA recep-
tors and voltage-gated calcium channels. Currently, several
laboratories across the world are investigating the mode of
Mitochondrial Structural Studies neuroprotective action of dimebon in neurodegenerative
Recent studies of mitochondrial structure in brain tis- diseases by investigating cell and mouse models of neurode-
sue from Alzheimer's disease patients and neuronal cells generative diseases, including Alzheimer's disease and HD.
expressing mutant APP found that Ap fragments mito-
chondria and causes structural changes in neurons from Conclusion
Alzheimer's disease patients.3537
Increasing evidence suggests that mitochondrial dysfunc-
tion is involved in aging, cancer, diabetes, and neurodegenera-
Mitochondrial Therapeutics tive diseases. Age-dependent accumulation of mitochondrial
Synaptic damage and mitochondrial dysfunction have abnormalities and mutant proteins lead to both structural and
been reported as early pathogenic events associated with functional changes in neuronal function and to cell death. In
aging, neurodegenerative diseases, cancer, and diabetes. addition to aging, epigenetic factors and lifestyle activities
It may be possible to treat these pathogenic events by may likely contribute to neurodegeneration and cell death.
developing molecules that treat mitochondria (targeting Furthermore, in Alzheimer's disease, mutant APP and Ap enter
ROS). These molecules decrease free radical production mitochondria and/or block the transport of nuclear-encoded
and oxidative damage, and boost overall mitochondrial mitochondrial proteins to mitochondria, in turn inducing free
function, which ultimately increases synaptic branching radicals, increasing oxidative damage, and causing cell death.
of neurons. Also, treatments may function by therapeuti- Through studies that are elucidating the role of mitochondria
cally boosting ATP levels in mitochondria that ultimately in disease onset and development, investigators have begun
increases synaptic outgrowth and neuronal connectivity. focusing research efforts on developing therapies, such as
Given the huge involvement of mitochondrial dysfunction molecules that target and protect mitochondria and neurons
in aging and neurodegenerative diseases, it is reasonable from the toxicity aging and mutant proteins. Progress is
to treat or supplement the diet with antioxidants in patients being made in this research, and there is hope that significant
with neurodegenerative diseases such as Alzheimer's dis- steps can continue, which could create a future when such
ease, Parkinson's disease, and HD. However, recent intake diseases as Alzheimer's disease, Parkinson's disease, cancer,
of natural antioxidants to Alzheimer's disease patients gave and diabetes, can be better controlled.
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23. Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting
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