The overall aim of this article is to review current therapeuticstrategies for treating AD, with a focus on mitochondriallytargeted antioxidant treatments. Recent advances in molecular,cellular, and animal model studies of AD have revealed thatamyloid precursor protein derivatives, including amyloid beta <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>A</mml:mi><mml:mi>&#x03B2;</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:math> monomers and oligomers, are likely key factors in tauhyperphosphorylation, mitochondrial oxidative damage, inflammatorychanges, and synaptic failure in the brain tissue of AD patients.Several therapeutic strategies have been developed to treat AD,including anti-inflammatory, antioxidant, and antiamyloidapproaches. Among these, mitochondrial antioxidant therapy hasbeen found to be the most efficacious in reducing pathologicalchanges and in not producing adverse effects; thus, mitochondrialantioxidant therapy is promising as a treatment for AD patients.However, a major limitation in applying mitochondrial antioxidantsto AD treatment has been the inability of researchers to enhanceantioxidant levels in mitochondria. Recently, however, there hasbeen a breakthrough. Researchers have recently been able topromote the entry of certain antioxidants&#8212;including MitoQ,MitoVitE, MitoPBN, MitoPeroxidase, and amino acid andpeptide-based SS tetrapeptides&#8212;into mitochondria, severalhundred-fold more than do natural antioxidants. Once in themitochondria, they rapidly neutralize free radicals and decreasemitochondrial toxicity. Thus, mitochondrially targetedantioxidants are promising candidates for treating AD patients.

P. Hemachandra Reddy

Mitochondrial Oxidative Damage in Aging and Alzheimer&#39;s Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics

Extensive <mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>-amyloid (A<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>) deposits in brain parenchyma
in the form of senile plaques and in blood vessels in the form of
amyloid angiopathy are pathological hallmarks of Alzheimer's
disease (AD). The mechanisms underlying A<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> deposition
remain unclear. Major efforts have focused on A<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> production,
but there is little to suggest that increased production of
A<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> plays a role in A<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> deposition, except for rare
familial forms of AD. Thus, other mechanisms must be involved in
the accumulation of A<mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> in AD. Recent data shows that
impaired clearance may play an important role in A<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>
accumulation in the pathogenesis of AD. This review focuses on our
current knowledge of A<mml:math id="E10" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>-degrading enzymes, including
neprilysin (NEP), endothelin-converting enzyme (ECE),
insulin-degrading enzyme (IDE), angiotensin-converting enzyme
(ACE), and the plasmin/uPA/tPA system as they relate to amyloid
deposition in AD.

Deng-Shun Wang

Dennis W. Dickson

James S. Malter


	<svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
		<g transform="matrix(.017,-0,0,-.017,.062,12.162)">
			<path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5 t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z"/>
		</g>
	</svg>-Amyloid Degradation and Alzheimer's Disease


Cytosolic brain-type creatine kinase (BB-CK), which is coexpressed
with ubiquitous mitochondrial uMtCK, is significantly inactivated
by oxidation, in Alzheimer's disease (AD) patients. Since CK has
been shown to play a fundamental role in cellular energetics of
the brain, any disturbance of this enzyme may exasperate the AD
disease process. Mutations in amyloid precursor protein (APP) are
associated with early onset AD and result in abnormal processing
of APP, and accumulation of A<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> peptide, the main
constituent of amyloid plaques in AD brain. Recent data on a
direct interaction between APP and the precursor of uMtCK support
an emerging relationship between AD, cellular energy levels and
mitochondrial function. In addition, recently discovered creatine
(Cr) deposits in the brain of transgenic AD mice, as well as in
the hippocampus from AD patients, indicate a direct link between
perturbed energy state, Cr metabolism and AD. Here, we review the
roles of Cr and Cr-related enzymes and consider the potential
value of supplementation with Cr, a potent neuroprotective
substance. As a hypothesis, we consider whether Cr, if given at an
early time point of the disease, may prevent or delay the course
of AD-related neurodegeneration.

Tanja S. Bürklen

Uwe Schlattner

Ramin Homayouni

Kathleen Gough

Margaret Rak

Adriana Szeghalmi

Theo Wallimann

The Creatine Kinase/Creatine Connection to Alzheimer's
    Disease: CK Inactivation, APP-CK Complexes  and
    Focal Creatine Deposits

Amyloid peptide (A<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>) aggregates, derived from initial
<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>-site proteolytic processing of the amyloid precursor
protein (APP), accumulate in the brains of Alzheimer's disease
patients. The plasmin-generating cascade appears to serve a
protective role in the central nervous system since
plasmin-mediated proteolysis of APP utilizes the <mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>
 site,
eventually generating nontoxic peptides, and plasmin also degrades
A<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>. The conversion of plasminogen to plasmin by tissue-type
plasminogen activator in the brain is negatively regulated by
plasminogen activator inhibitor type-1 (PAI-1) resulting in
attenuation of plasmin-dependent substrate degradation with
resultant accumulation of A<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>. PAI-1 and its major
physiological inducer TGF-<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:math>, moreover, are increased in
models of Alzheimer's disease and have been implicated in the
etiology and progression of human neurodegenerative disorders.
This review highlights the potential role of PAI-1 and TGF-<mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:math> in this process. Current molecular events associated with
TGF-<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:math>-induced PAI-1 transcription are presented with
particular relevance to potential targeting of PAI-1 gene
expression as a molecular approach to the therapy of
neurodegenerative diseases associated with increased PAI-1
expression such as Alzheimer's disease.

Paul J. Higgins

The TGF-<svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
		<g transform="matrix(.017,-0,0,-.017,.062,12.162)">
			<path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5
t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z"/>
		</g>
	</svg> 1/Upstream Stimulatory Factor-Regulated PAI-1 Gene:
Potential Involvement and a Therapeutic Target  in Alzheimer's
Disease


Individuals suffering from human immunodeficiency virus type 1
(HIV-1) infection suffer from a wide range of neurological
deficits. The most pronounced are the motor and cognitive deficits
observed in many patients in the latter stages of HIV infection.
Gross postmortem inspection shows cortical atrophy and widespread
neuronal loss. One of the more debilitating of the HIV-related
syndromes is AIDS-related dementia, or HAD. Complete understanding
of HIV neurotoxicity has been elusive. Both direct and indirect
toxic mechanisms have been implicated in the neurotoxicity of the
HIV proteins, Tat and gp120. The glutamatergic system, nitric
oxide, calcium, oxidative stress, apoptosis, and microglia have all
been implicated in the pathogenesis of HIV-related neuronal
degeneration. The aim of this review is to summarize the most
recent work and provide an overview to the current theories of
HIV-related neurotoxicity and potential avenues of therapeutic
interventions to prevent the neuronal loss and motor/cognitive
deficits previously described.

David R. Wallace

HIV Neurotoxicity: Potential Therapeutic Interventions

Protein synthesis and protein degradation are highly regulated
cellular processes that are essential to maintaining cell
viability. Numerous studies now indicate that protein synthesis
and protein degradation are significantly altered in Alzheimer's
disease (AD), with impairments in these two processes potentially
contributing to AD pathogenesis. Alterations in steady state
protein regulation may be a particularly important factor in
regulating whether cells maintain homeostasis in response to
oxidative damage, or conversely whether oxidative stress is
induced by oxidative damage. The focus of this review is to
discuss recent findings on each of these topics, and to discuss
their importance to the onset and progression of AD.

Jeffrey N. Keller

Interplay Between Oxidative Damage, Protein Synthesis, and Protein
Degradation in Alzheimer's Disease

Studies during the last two decades have provided new insights
into the molecular mechanism of Alzheimer's disease (AD). One of
the milestone findings in AD research was the demonstration that
neurofibrillary degeneration characterized by tau pathology is
central to the pathogenesis of AD and other tauopathies and that
abnormal hyperphosphorylation of tau is pivotal to neurofibrillary
degeneration. This article reviews the recent research advances in
tau pathology and the underlying dysregulation of the protein
phosphorylation/dephosphorylation system. An updated model of the
mechanism of neurofibrillary degeneration is also presented, and a
promising therapeutic target to treat AD by correcting
dysregulation of protein phosphorylation/dephosphorylation is
discussed.

Cheng-Xin Gong

Fei Liu

Inge Grundke-Iqbal

Khalid Iqbal

Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic Target

Protein aggregation takes place in many neurodegenerativedisorders. However, there is a controversy about the possibletoxicity of these protein aggregates. In this review, thiscontroversy is discussed, focussing on the tau aggregation thattakes place in those disorders known as tauopathies.

J.  Avila

I.  Santa-Mar&#237;a

M.  P&#233;rez

F.  Hern&#225;ndez

F.  Moreno

Tau Phosphorylation, Aggregation, and Cell Toxicity

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BioMed Research International

Neurodegenerative Diseases: Mechanisms and Therapies

Neurodegenerative Diseases: Mechanisms and Therapies

Articles

Mitochondrial Oxidative Damage in Aging and Alzheimer's Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics

-Amyloid Degradation and Alzheimer's Disease

The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK Inactivation, APP-CK Complexes and Focal Creatine Deposits

The TGF- 1/Upstream Stimulatory Factor-Regulated PAI-1 Gene: Potential Involvement and a Therapeutic Target in Alzheimer's Disease

HIV Neurotoxicity: Potential Therapeutic Interventions

Interplay Between Oxidative Damage, Protein Synthesis, and Protein Degradation in Alzheimer's Disease

Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic Target

Tau Phosphorylation, Aggregation, and Cell Toxicity