Mark A. Smith and George Perry
Case Western Reserve University, Institute of
Pathology, 2085 Adelbert Road, Cleveland, Ohio 44106, USA
Oxidative damage not only occurs to the proteins
comprising the lesions of Alzheimer disease, neurofibrillary tangles and
senile plaques, but also precedes lesion formation in neurons at risk of
death during the disease. While oxidative stress may not be the primary
etiology of the disease, it precedes specific cellular and tissue damage
that underlies the onset of dementia. Our assertion links Alzheimer disease
to normal aging where oxidative stress has been implicated. Further, our
idea is supported by epidemiological data linking the prevalence of Alzheimer
disease to diet, an established link to longevity. Additionally, the proteins
known from genetics to play a role in AD such as beta protein precursor,
apolipoprotein E or presenilins either regulate apoptosis or bind transition
metals - both important mechanisms related to oxidative stress. The clinical
efficacy of reducing oxidative stress in Alzheimer disease is highlighted
by the reduction in prevalence and progression by agents such as nonsteroidal
anti-inflammatories, estrogen, and vitamin E which all share the one common
feature of reducing oxidative stress.
Therefore, we suggest that oxidative stress is
a central feature of the pathogenesis of Alzheimer disease and that treatments
that specifically target sources of oxygen radicals may have particular
therapeutic efficacy. Specifically, we suggest two broad based treatment
strategies, based on preventing the generation of or ameliorating the effects
of oxidative stress will be particularly effective.
1. Transition Metal Chelation Therapy:
For example, deferoxamine or its derivatives.
2. Dietary Modification: Either (i) the
development of water- and fat-soluble antioxidant approaches to increase
antioxidants or (ii) reduce total calories and calories from fat.
Studies over the past five years have established
oxidative stress and damage not only in the lesions of Alzheimer disease
but also in neurons at risk of death (Smith et al., 1994a,b, 1995a-c, 1996a,b,
1997a,b; Sayre et al., 1997a). Current studies are establishing how oxidative
stress is related to other possible causes of Alzheimer disease as well
as whether oxidative stress is an initiator or is instead a result of the
disease process (Figure 1). The distinction of where oxidative stress lies
in this scheme is more than academic since it is essential to know whether
reducing oxidative stress will have therapeutic value to protect brain
function. Here we present evidence that oxidative damage is the earliest
cytopathological marker of neuronal dysfunction in Alzheimer disease and,
moreover, impinges on all proposed pathogenic risk factors and mechanisms
implicated in Alzheimer disease.
The pathological presentation of Alzheimer disease,
the leading cause of senile dementia, involves regionalized neuronal death
and an accumulation of intraneuronal and extracellular lesions termed neurofibrillary
tangles and senile plaques, respectively (reviewed in Smith, 1997). Several
independent hypotheses have been proposed to link the pathological lesions
and neuronal cytopathology with, among others, apolipoprotein E genotype
(Corder et al., 1993; Roses, 1995); hyperphosphorylation of cytoskeletal
proteins (Trojanowski et al., 1993a), and amyloid-ß metabolism (Selkoe,
1997). However, not one of these theories alone is sufficient to explain
the diversity of biochemical and pathological abnormalities of Alzheimer
disease which involves a multitude of cellular and biochemical changes.
Furthermore, attempts to mimic the disease by a perturbation of one of
these elements using cell or animal models, including transgenic animals,
do not result in the same spectrum of pathological alterations. The most
striking case is that while amyloid-ß plaques are deposited in some
transgenic rodent models overexpressing ß-protein precursor (Hsiao
et al., 1996), there is no neuronal loss - a seminal feature of Alzheimer
What many of these theories have failed to incorporate
is that Alzheimer disease is a disease of aging (Katzman, 1986). Importantly,
this holds true even in individuals with a genetic predisposition, i.e.,
those individuals with an autosomal dominant inheritance of Alzheimer disease
or in individuals with Downs syndrome who develop the pathology of Alzheimer
disease. Therefore, age is a clear contributor in 100% of Alzheimer disease
cases, whatever the genetic background. The free radical theory of aging
(Harman, 1956), hypothesizes that the aging process is associated with
(i) an increase in the adventitious production of oxygen-derived radicals,
i.e., reactive oxygen species (ROS), together with (ii) a concurrent decrease
in the ability to defend against such ROS that leads to the accumulation
of oxidatively-modified macromolecules. The decrease in ROS buffering capacity
also leads to a compromised ability to deal with abnormal sources of ROS
such as those associated with genetic predisposition and/or disease status.
Oxygen Radical Generation and Oxidative Stress
in Alzheimer Disease
ROS production occurs as a ubiquitous byproduct
of both oxidative phosphorylation and the myriad of oxidases necessary
to support aerobic metabolism. In Alzheimer disease, in addition to this
background level of ROS, there are a number of additional contributory
sources that are thought to play an important role in the disease process:
(1) Iron, in a redox-active state, is increased in neurofibrillary tangles
as well as in amyloid-ß deposits (Good et al., 1992; Smith et al,
1997a). Iron catalyzes the formation of OH from H2O2
as well as the formation of advanced glycation end products. Furthermore,
aluminum, which also accumulates in neurofibrillary tangle-containing neurons
(Good et al., 1992), stimulates iron-induced lipid peroxidation (Oteiza,
1994). (2) Activated microglia, such as those that surround most senile
plaques (Cras et al., 1990), are a source of NO and O2-
(Colton and Gilbert, 1987) which can react to form peroxynitrite, leaving
nitrotyrosine as an identifiable marker (Good et al., 1996; Smith et al.,
1997b). (3) Amyloid-ß itself has been directly implicated in ROS
formation through peptidyl radicals (Butterfield et al., 1994; Hensley
et al., 1994; Sayre et al., 1997b). (4) Advanced glycation end products
in the presence of transition metals (see above) can undergo redox cycling
with consequent ROS production (Baynes, 1991; Yan et al., 1994, 1995).
Additionally, advanced glycation end products and amyloid-ß activate
specific receptors such as the receptor for advanced glycation end products
(RAGE) and the class A scavenger-receptor to increase ROS production (Yan
et al., 1996; El Khoury et al., 1996). (5) Abnormalities in mitochondrial
metabolism, such as deficiencies in key enzyme function, resulting in part
from detection of the mitochondrial genome, suggest the mitochondria may
be the major and possible initiating source of ROS (Davis et al., 1997).
An exact determination of the contribution of
each source of oxidative stress is complicated if for no other reason than
that most sources have positive feedback. Nonetheless, the overall result
is damage including advanced glycation end products (Smith et al., 1994a),
nitration (Smith et al., 1997b), lipid peroxidation adduction products
(Sayre et al., 1997a) as well as carbonyl-modified neurofilament protein
and free carbonyls (Smith et al., 1991; Smith et al., 1994a, 1995b, 1996a;
Ledesma et al., 1994; Vitek et al., 1994; Yan et al., 1994; Montine et
al., 1996a; Sayre et al., 1997a) with the involvement extending beyond
the lesions to neurons not displaying obvious degenerative change. Oxidative
crosslinking makes proteins not only insoluble (reviewed in Smith et al.,
1995a; Smith et al., 1996b) but also resistant to proteolytic removal (Cras
et al., 1995) by competitively inhibiting the proteosome (Friguet et al.,
1994). Therefore, oxidative crosslinking may be significant in the accumulation
of ubiquitin conjugates in neurofibrillary tangles (Perry et al., 1987)
in the face of numerous proteolytic activities which are highly active
against abnormal proteins (Smith and Perry, 1994). Indeed, it may not be
coincidental that fibrillary inclusions found in neurodegenerative diseases
other than Alzheimer disease are also extensively ubiquinated, e.g., Lewy/Pick
bodies and Rosenthal fibers (Galloway et al., 1988; Manetto et al., 1989)
and are also oxidatively modified (Castellani et al., 1995, 1996, 1997).
The cytopathological significance of oxidative
damage is seen by the upregulation of the antioxidant enzyme heme oxygenase-1
in neurons with NFT (Smith et al., 1994b; Premkumar et al., 1995). Furthermore,
in quantitative immunocytochemical studies, there is a complete overlap
between heme oxygenase-1 and Alz50, an early marker of tau abnormalities,
indicating that cytoskeletal abnormalities are associated with increased
oxidative stress or vice versa (Smith and Perry, unpublished observation).
Is Oxidative Stress the Process that Ties Together
the Seemingly Separable Events of Alzheimer Disease?
Age-related increases in oxidative stress may
be the major contributor toward all aspects of Alzheimer disease. In other
words, oxidative stress may provide a link between all of the currently
accepted views regarding disease pathogenesis (Figure 2).
Oxidative Stress And Cytoskeletal Phosphorylation:
The mechanisms by which normal soluble cytoskeletal elements, such as tau
and neurofilaments, are transformed into insoluble paired helical filaments
is an important issue (Selkoe et al., 1982; Smith et al., 1996b). Insolubility
has been linked to the most well known posttranslational change of tau,
abnormal phosphorylation (Goedert et al., 1991; Greenberg et al., 1992)
and a number of specific kinases and phosphatases have been implicated
(reviewed in Trojanowski et al., 1993a). However, while increased phosphorylation
decreases microtubule stability, a salient feature of the pathology of
Alzheimer disease (Perry et al., 1991; Alonso et al., 1994, 1996; Iqbal
et al., 1994; Praprotnik et al., 1996a,b), NFT insolubility is not mediated
by phosphorylation (Smith et al., 1996b). Indeed, in vitro phosphorylation
of normal tau or complete dephosphorylation of NFT has no effect on their
solubility (Goedert et al., 1991; Greenberg et al., 1992; Gustke et al.,
1992; Smith et al., 1996b). Instead, recent studies suggest tau phosphorylation
as found in Alzheimer disease may be part of a novel process similar to
that seen during mitosis (Pope et al., 1994; Preuss et al., 1995) suggesting
that it might be abortively entering the cell cycle (Vincent et al., 1996;
McShea et al., 1997).
Phosphorylation is intimately tied to oxidative
stress by the mitogen activated phosphorylation (MAP) pathway (Guyton et
al., 1996) as well as through activation of transcription factor NFkB (Schreck
et al., 1991). While there is controversy concerning the kinases involved
in the phosphorylation of tau in Alzheimer disease, the MAP kinase pathway
is implicated (Ledesma et al., 1992; Trojanowski et al., 1993b; Hyman et
al., 1994). Therefore, abnormal phosphorylation of proteins in Alzheimer
disease may be a consequence of oxidative stress and it is perhaps not
surprising that while all pyramidal neurons of the hippocampus show increased
free carbonyls (Smith et al., 1996a), lipid peroxide adduction (Sayre et
al., 1997a) and nitrotyrosine (Smith et al., 1997b) only a subset of neurons
displaying overt degeneration also show increased phosphorylation (Sternberger
et al., 1985; Grundke-Iqbal et al., 1986). Heme oxygenase-1, an inducible
antioxidant enzyme, also shows the same pattern of involvement since it
accumulates concurrent with phosphorylated tau (Smith and Perry, unpublished
data). Therefore, induction of the kinase and oxidative stress responses
appears to require the same critical level of oxidative damage (Premkumar
et al., 1995).
Influences of Amyloid-ß and Other Genetic
Factors on Oxidative Stress: A number of mechanisms have been invoked
for the neurotoxicity of amyloid-ß (Yankner et al., 1990; reviewed
in Iversen et al., 1995; Sayre et al., 1997b) including membrane depolarization
(Carette et al., 1993), increased sensitivity to excitotoxins (Koh et al.,
1990), and alterations in calcium homeostasis (Mattson et al., 1992). However,
the leading hypothesis is that neuronal damage by amyloid-ß is mediated
by free radicals and, as such, can be attenuated using antioxidants such
as vitamin E (Behl et al., 1992, 1994) or catalase (Zhang et al., 1996)
although there has been some controversy regarding whether the protection
from the latter involves its antioxidant activity (Lockhart et al., 1994).
Critically addressing whether amyloid-ß initiates oxidative damage
in Alzheimer disease requires careful study of the relationship of amyloid-ß
deposition and increased oxidative damage. In this regard, it will be extremely
interesting to determine the oxidative status of the recently reported
transgenic rodent models of amyloid-ß deposition (Games et al., 1995;
Hsiao et al., 1996).
Mutations in ßPP are the cause of Alzheimer
disease in a small number of familial cases where the mutations lead to
increased amyloid-ß deposition (reviewed in Selkoe, 1996, 1997).
Transgenic rodents overexpressing ßPP, which display many of the
neuropathological correlates of Alzheimer disease, support the important
role of amyloid-ß (Games et al., 1995; Hsiao et al., 1996). It is
interesting to consider that ßPP/amyloid-ß may be related to
oxidative stress. Indeed, amyloid-ß is reported to spontaneously
generate peptidyl radicals (Butterfield et al., 1994; Goodman et al., 1994;
Harris et al., 1995; Prehn et al., 1996). Further, mutations in ßPP
are associated with increased DNA fragmentation, possibly involving oxidative
mechanisms (see below).
Presenilins 1 and 2 (Sherrington et al., 1995;
Selkoe, 1997) are genetic factors where the biological mechanism, although
not established, may also involve oxidative damage. Increased presenilin
2, expression increases DNA fragmentation and apoptotic changes (Wolozin
et al., 1996), both important consequences of oxidative damage. Apolipoprotein
E, in brains and cerebrospinal fluid, is found adducted with the highly
reactive lipid peroxidation product, hydroxynonenal (Montine et al., 1996b).
Furthermore, apolipoprotein E is a strong chelator of copper and iron,
important redox-active transition metals (Miyata and Smith, 1996). Finally,
interaction of apolipoprotein E with amyloid-ß only occurs in the
presence of oxygen (Strittmatter et al., 1993).
In programmed cell death, i.e., apoptosis, cells
are digested within their own membrane by proteases and nucleases as well
as by increased ROS. However, without the full range of morphological changes,
it is unclear whether DNA fragmentation is apoptotic or is, instead, mediated
solely by oxidative stress (Berlin and Haseltine, 1981). While the relative
contribution of oxidative stress and apoptosis related DNA fragmentation
is unresolved, the relative infrequency of apoptosis defined by morphology
(Su et al., 1994; Cotman and Su, 1996) and the broad findings of fragmentation
in all cells in cases of Alzheimer disease argues for widespread oxidative
DNA damage. Certainly, this interpretation is consistent with the oxidative
nuclear damage in all cells of the brain in areas affected in Alzheimer
disease (Smith et al, 1996a, 1997a).
An important question in discerning whether reducing
oxidative stress may have therapeutic value is whether it is a primary
or secondary event in disease pathogenesis (Mattson et al., 1995; Smith
et al., 1995c) (Figure 2). Recent evidence supports oxidative damage as
the earliest cytopathological and biochemical change of Alzheimer disease
(Ledesma et al., 1994; Smith et al., 1994a, 1995a, 1996a, 1997b; Vitek
et al., 1994; Yan et al., 1994; Sayre et al., 1997a).
Agents that inhibit free radical formation, reduce
both the incidence and the progression of Alzheimer disease (McGeer and
Rogers, 1992; Rogers et al., 1993; Rich et al., 1995; Stewart et al., 1997).
For the latter, several studies have found epidemiological relationships
(Breitner et al., 1994; McGeer and Rogers, 1992) that, together with the
results of metal chelation treatment (McLachlan et al., 1991), strongly
suggest that oxidative stress precedes cell and tissue damage and therefore
agents that prevent oxidative damage show promise in the treatment of Alzheimer
Oxidative stress may underline all of the commonly
accepted notions on Alzheimer disease pathogenesis, including hyperphosphorylation,
apolipoprotein E genotype, and mutations of the ß-protein precursor.
Further studies, to examine the types and extent of oxidative damage, will
undoubtedly identify which antioxidant agents will prove most efficacious
in the treatment of Alzheimer disease.
Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. and
Iqbal, K. (1994). Role of abnormally phosphorylated tau in the breakdown
of microtubules in Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 5562-5566.
Alonso, A. C., Grundke-Iqbal, I. and Iqbal, K.
(1996). Alzheimer's disease hyperphosphorylated tau sequesters normal tau
into tangles of filaments and disassembles microtubules. Nature Med. 2,
Baynes, J. W. (1991). Role of oxidative stress
in development of complications in diabetes. Diabetes 40, 405-412.
Behl, C., Davis, J., Cole, G. M. and Schubert,
D. (1992). Vitamin E protects nerve cells from amyloid-ß protein
toxicity. Biochem. Biophys. Res. Commun. 186, 944-950.
Behl, C., Davis, J. B., Lesley, R. and Schubert,
D. (1994). Hydrogen peroxide mediates amyloid ß protein toxicity.
Cell 77, 817-827.
Berlin, V. and Haseltine, W. A. (1981). Reduction
of adriamycin to a semiquinone-free radical by NADPH cytochrome P-450 reductase
produces DNA cleavage in a reaction mediated by molecular oxygen. J. Biol.
Chem. 256, 4747-4756.
Breitner, J. C. S., Gau, B. A., Welsh, K. A.,
Plassman, B. L., McDonald, W. M., Helms, M. J. and Anthony, J. C. (1994).
Inverse association of anti-inflammatory treatments and Alzheimer's disease:
initial results of a co-twin control study. Neurology 44, 227-232.
Butterfield, D. A., Hensley, K., Harris, M., Mattson,
M. and Carney, J. (1994). ß-amyloid peptide free radical fragments
initiate synaptosomal lipoperoxidation in a sequence-specific fashion:
implications to Alzheimer's disease. Biochem. Biophys. Res. Commun. 200,
Carette, B., Poulain, P. and Delacourte, A. (1993).
Electrophysiological effects of 25-35 amyloid- ß-protein on guinea-pig
lateral septal neurons. Neurosci. Lett. 151, 111-114.
Castellani, R., Smith, M. A., Richey, P. L., Kalaria,
R., Gambetti, P. and Perry, G. (1995). Evidence for oxidative stress in
Pick disease and corticobasal degeneration. Brain Res. 696, 268-271.
Castellani, R., Smith, M. A., Richey, P. L. and
Perry, G. (1996). Glycoxidation and oxidative stress in Parkinson disease
and diffuse Lewy body disease. Brain Res. 737, 195-200.
Castellani, R. J., Perry, G., Harris, P. L. R.,
Monnier, V. M., Cohen, M. L. and Smith, M. A. (1997). Advanced glycation
modification of Rosenthal fibers in Alexander disease. Neurosci. Lett.
Colton, C. A. and Gilbert, D. L. (1987). Production
of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 223,
Corder, E. H., Saunders, A. M., Strittmatter,
W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines,
J. L. and Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type
4 allele and the risk of Alzheimer's disease in late onset families. Science
Cotman, C. W. and Su, J. H. (1996). Mechanisms
of neuronal death in Alzheimer's disease. Brain Pathol. 6, 493-506.
Cras, P., Kawai, M., Siedlak, S., Mulvihill, P.,
Gambetti, P., Lowery, D., Gonzalez-DeWhitt, P., Greenberg, B. and Perry,
G. (1990). Neuronal and microglial involvement in ß-amyloid protein
deposition in Alzheimer's disease. Am. J. Pathol. 137, 241-246.
Cras, P., Smith, M. A., Richey, P. L., Siedlak,
S. L., Mulvihill, P. and Perry, G. (1995). Extracellular neurofibrillary
tangles reflect neuronal loss and provide further evidence of extensive
protein cross-linking in Alzheimer disease. Acta Neuropathol. 89, 291-295.
Davis, R. E., Miller, S., Herrnstadt, C., Ghosh,
S. S., Fahy, E., Shinobu, L. A., Galasko, D., Thal, L. J., Beal, M. F.,
Howell, N. and Parker, W. D. Jr. (1997). Mutations in mitochondrial cytochrome
c oxidase genes segregate with late-onset Alzheimer disease. Proc. Natl.
Acad. Sci. USA 94, 4526-4531.
El Khoury, J., Hickman, S. E., Thomas, C. A.,
Cao, L., Silverstein, S. C. and Loike, J. D. (1996). Scavenger receptor-mediated
adhesion of microglia to ß-amyloid fibrils. Nature 382, 716-719.
Friguet, B., Stadtman, E. R. and Szweda, L. I.
(1994). Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal.
Formation of cross-linked protein that inhibits the multicatalytic protease.
J. Biol. Chem. 269, 21639-21643.
Galloway, P. G., Grundke-Iqbal, I., Iqbal, K.
and Perry, G. (1988). Lewy bodies contain epitopes both shared and distinct
from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol 47, 654-663.
Games, D., Adams, D., Alessandrini, R., Barbour,
R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T.,
Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee,
M., Leibowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue,
L., Montoya-Zavala, M., Mucke, L., Paganini, L., Penniman, E., Power, M.,
Schenk, D., Seubert, P., Snyer, B., Soriano, F., Tan, H., Vitale, J., Wadsworth,
S., Wolozin, B. and Zhao, J. (1995). Alzheimer-type neuropathology in transgenic
mice overexpressing V717F ß-amyloid precursor protein. Nature 373,
Goedert, M., Sisodia, S. S. and Price, D. L. (1991).
Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease.
Curr. Opin. Neurobiol. 1, 441-447.
Good, P. F., Perl, D. P., Bierer, L. M. and Schmeidler,
J. (1992) Selective accumulation of aluminum and iron in the neurofibrillary
tangles of Alzheimer's disease: a laser microprobe (LAMMA) study. Ann.
Neurol. 31, 286-292.
Good, P. F., Werner, P., Hsu, A., Olanow, C. W.
and Perl, D. P. (1996). Evidence of neuronal oxidative damage in Alzheimer's
disease. Am. J. Pathol. 149, 21-28.
Goodman, Y., Steiner, M. R., Steiner, S. M. and
Mattson, M. P. (1994). Nordihydroguaiaretic acid protects hippocampal neurons
against amyloid beta-peptide toxicity, and attenuates free radical and
calcium accumulation. Brain Res. 654, 171-176.
Greenberg, S. G., Davies, P., Schein, J. D. and
Binder, L. I. (1992). Hydrofluoric acid-treated tau PHF proteins display
the same biochemical properties as normal tau. J. Biol. Chem. 267, 564-569.
Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan,
M., Wisniewski, H. M. and Binder, L. I. (1986). Abnormal phosphorylation
of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology.
Proc. Natl. Acad. Sci. USA 83, 4913-4917.
Gustke, N., Steiner, B., Mandelkow, E. M., Biernat,
J., Meyer, H. E., Goedert, M. and Mandelkow, E. (1992). The Alzheimer-like
phosphorylation of tau protein reduces microtubule binding and involves
Ser-Pro and Thr-Pro motifs. FEBS Lett. 307, 199-205.
Guyton, K. Z., Liu, Y., Gorospe, M., Xu, Q. and
Holbrook, N. J. (1996). Activation of mitogen-activated protein kinase
by H2O2. Role in cell survival following oxidant
injury. J. Biol. Chem. 271, 4138-4142.
Harman, D. (1956). Ageing: a theory based on free
radical and radiation chemistry. J. Gerontol. 11, 298-300.
Harris, M. E., Carney, J. M., Cole, P. S., Hensley,
K., Howard, B. J., Martin, L., Bummer, P., Wang, Y., Pedigo, N. W. J. and
Butterfield, D. A. (1995). ß-amyloid peptide-derived, oxygen-dependent
free radicals inhibit glutamate uptake in cultured astrocytes: implications
for Alzheimer's disease. Neuroreport 6, 1875-1879.
Hensley, K., Carney, J. M., Mattson, M. P., Aksenova,
M., Harris, M., Wu, J. F., Floyd, R. A., and Butterfield, D. A. (1994).
A model for ß-amyloid aggregation and neurotoxicity based on free
radical generation by the peptide: relevance to Alzheimer disease. Proc.
Natl. Acad. Sci. USA 91, 3270-3274.
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C.,
Harigaya, Y., Younkin, S., Yang, F. and Cole, G. (1996). Correlative memory
deficits, Aß elevation, and amyloid plaques in transgenic mice. Science
Hyman, B. T., Elvhage, T. E. and Reiter, J. (1994).
Extracellular signal regulated kinases. Localization of protein and mRNA
in the human hippocampal formation in Alzheimers disease. Am. J. Pathol.
Iqbal, K., Zaidi, T., Bancher, C. and Grundke-Iqbal,
I. (1994). Alzheimer paired helical filaments. Restoration of the biological
activity by dephosphorylation. FEBS Lett. 349, 104-108.
Iversen, L. L., Mortishire-Smith, R. J., Pollack,
S. J. and Shearman, M. S. (1995). The toxicity in vitro of ß-amyloid
protein. Biochem. J. 331, 1-16. Katzman, R. (1986). Alzheimer's disease.
N. Engl. J. Med. 314, 964-973.
Katzman, R. (1986). Alzheimer's disease. N. Engl.
J. Med., 314, 964-973.
Koh, J. Y., Yang, L. L. and Cotman, C. W. (1990).
ß-amyloid protein increases the vulnerability of cultured cortical
neurons to excitotoxic damage. Brain Res. 533, 315-320.
Ledesma, M. D., Correas, I., Avila, J. and Diaz-Nido,
J. (1992). Implication of brain cdc2 and MAP2 kinases in the phosphorylation
of tau protein in Alzheimer's disease. FEBS Lett. 308, 218-224.
Ledesma, M. D., Bonay, P., Colaco, C. and Avila,
J. (1994). Analysis of microtubule-associated protein tau glycation in
paired helical filaments. J. Biol. Chem. 269, 21614-21619.
Lockhart, B. P., Benicourt, C., Junien, J. L.
and Privat, A. (1994). Inhibitors of free radical formation fail to attenuate
direct ß-amyloid25-35 peptide-mediated neurotoxicity in
rat hippocampal cultures. J. Neurosci. Res. 39, 494-505.
Manetto, V., Abdul-Karim, F. W., Perry, G., Tabaton,
M., Autilio-Gambetti, L. and Gambetti, P. (1989). Selective presence of
ubiquitin in intracellular inclusions. Am J Pathol 134, 505-513.
Mattson, M. P., Cheng, B., Davis, D., Bryant,
K., Lieberburg, I. and Rydel, R. E. (1992). ß-amyloid peptides destabilize
calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.
J. Neurosci. 12, 376-389.
Mattson, M. P., Carney, J. W. and Butterfield,
D. A. (1995). A tombstone in Alzheimer's? Nature 373, 481. McGeer, P. L.
and Rogers, J. (1992). Anti-inflammatory agents as a therapeutic approach
to Alzheimer's disease. Neurology 42, 447-449.
McLachlan, D. R., Kruck, T. P., Lukiw, W. J. and
Krishnan, S. S. (1991). Would decreased aluminum ingestion reduce the incidence
of Alzheimer's disease? Can. Med. Assoc. J. 145, 793-804.
McGeer, P. L., and Rogers, J. (1992). Anti-inflammatory
agents as a therapeutic approach to Alzheimer's disease. Neurology, 42,
McShea, A., Harris, P. L. R., Webster, K. R.,
Wahl, A., and Smith, M. A. (1997). Abnormal expression of the cell cycle
regulators P16 and CDK4 in Alzheimer's disease. Am. J. Pathol. 150, 1933-1939.
Miyata, M. and Smith, J. D. (1996). Apolipoprotein
E allelle-specific antioxidant activity and effects on cytotoxicity by
oxidative insults and ß-amyloid peptides. Nature Genetics 14, 55-61.
Montine, T. J., Amarnath, V., Martin, M. E., Strittmatter,
W. J. and Graham, D. G. (1996a). E-4-hydroxy-2-nonenal is cytotoxic and
cross-links cytoskeletal proteins in P19 neuroglial cultures. Am. J. Pathol.
Montine, T. J., Huang, D. Y., Valentine, W. M.,
Amarnath, V., Saunders, A., Weisgraber, K. H., Graham, D. G., and Strittmatter,
W. J. (1996b). Crosslinking of apolipoprotein E by products of lipid peroxidation.
J. Neuropathol. Exp. Neurol. 55, 202-210.
Oteiza, P. I. (1994). A mechanism for the stimulatory
effect of aluminum on iron-induced lipid peroxidation. Arch. Biochem. Biophys.
Perry, G., Friedman, R., Shaw, G. and Chau, V.
(1987). Ubiquitin is detected in neurofibrillary tangles and senile plaque
neurites of Alzheimer disease brains. Proc. Natl. Acad. Sci. USA 81, 3033-3036.
Perry, G., Kawai, M., Tabaton, M., Onorato, M.,
Mulvihill, P., Richey, P., Morandi, A., Connolly, J. A. and Gambetti, P.
(1991). Neuropil threads of Alzheimer's disease show a marked alteration
of the normal cytoskeleton. J. Neurosci. 11, 1748-1755.
Pope, W. B., Lambert, M. P., Leypold, B., Seupaul,
R., Sletten, L., Krafft, G., and Klein, W. L. (1994). Microtubule-associated
protein tau is hyperphosphorylated during mitosis in the human neuroblastoma
cell line SH-SY5Y. Exp. Neurol. 126, 185-194.
Praprotnik, D., Smith, M. A., Richey, P. L., Vinters,
H. V. and Perry, G. (1996a). Plasma membrane fragility in dystrophic neurites
in senile plaques of Alzheimers disease: an index of oxidative stress.
Acta Neuropathol. 91, 1-5.
Praprotnik, D., Smith, M. A., Richey, P. L., Vinters,
H. V. and Perry, G. (1996b). Filament heterogeneity within the dystrophic
neurites of senile plaques suggests blockage of fast axonal transport in
Alzheimers disease. Acta Neuropathol. 91, 226-235.
Prehn, J. H., Bindokas, V. P., Jordan, J., Galindo,
M. F., Ghadge, G. D., Roos, R. P., Boise, L. H., Thompson, C. B., Krajewski,
S., Reed, J. C. and Miller, R. J. (1996). Protective effect of transforming
growth factor-ß 1 on ß-amyloid neurotoxicity in rat hippocampal
neurons. Mol. Pharmacol. 49, 319-328.
Premkumar, D. R. D., Smith, M. A., Richey, P.
L., Petersen, R. B., Castellani, R., Kutty, R. K., Wiggert, B., Perry,
G. and Kalaria, R. N. (1995). Induction of heme oxygenase-1 mRNA and protein
in neocortex and cerebral vessels in Alzheimers disease. J. Neurochem.
Preuss, U., Doring, F., Illenberger, S. and Mandelkow,
E. M. (1995). Cell cycle-dependent phosphorylation and microtubule binding
of tau protein stably transfected into Chinese hamster ovary cells. Mol.
Biol. Cell 6, 1397-1410.
Rich, J. B., Rasmusson, D. X., Folstein, M. F.,
Carson, K. A., Kawas, C. and Brandt, J. (1995). Nonsteroidal anti-inflammatory
drugs in Alzheimer's disease. Neurology 45, 51-55.
Rogers, J., Kirby, L. C., Hempelman, S. R., Berry,
D. L., McGeer, P. L., Kaszniak, A. W., Zalinski, J., Cofield, M., Mansukhani,
L., Willson, P. and Kogan, F. (1993). Clinical trial of indomethacin in
Alzheimer's disease. Neurology 43, 1609-1611.
Roses, A. D. (1995). On the metabolism of apolipoprotein
E and the Alzheimer diseases. Exp. Neurol. 132, 149-156.
Sayre, L. M., Zelasko, D. A., Harris, P. L. R.,
Perry, G., Salomon, R. G. and Smith, M. A. (1997a). 4-Hydroxynonenal-derived
advanced lipid peroxidation end products are increased in Alzheimers disease.
J. Neurochem. 68, 2092-2097.
Sayre, L. M., Zagorski, M. G., Surewicz, W. K.,
Krafft, G. A. and Perry, G. (1997b). Mechanisms of neurotoxicity associated
with amyloid b deposition and the role of free radicals in the pathogenesis
of Alzheimers disease. A critical appraisal. Chem. Res. Toxicol. 10, 518-526.
Schreck, R., Rieber, P. and Baeuerle, P. A. (1991).
Reactive oxygen intermediates as apparently widely used messengers in the
activation of the NF-kB transcription factor and HIV-1. EMBO J. 10, 2247-2258.
Selkoe, D. J., Ihara, Y. and Salazar, F. J. (1982).
Alzheimer's disease: insolubility of partially purified paired helical
filaments in sodium dodecyl sulfate and urea. Science 215, 1243-1245.
Selkoe, D. J. (1996). Amyloid beta-protein and
the genetics of Alzheimer's disease. J. Biol. Chem. 271, 18295-18298.
Selkoe, D. J. (1997). Alzheimer's disease: genotypes,
phenotypes, and treatments. Science 275, 630-631.
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva,
E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda,
T., Mar, L., Foncin, J. -F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero,
I., Pinessi, L., Polinsky, R. J., Wasco, W., Da Silva, H. A. R., Haines,
J. L., Pericak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E.,
Rommens, J. M. and St. George-Hyslop, P. H. (1995). Cloning of a gene bearing
missense mutations in early-onset familial Alzheimer's disease. Nature
Smith, C. D., Carney, J. M., Starke-Reed, P. E.,
Oliver, C. N., Stadtman, E. R., Floyd, R. A. and Marksberry, W. R. (1991).
Excess brain protein oxidation and enzyme dysfunction in normal aging and
in Alzheimer disease. Proc. Natl. Acad. Sci. USA 88, 10540-10543.
Smith, M.A. and Perry, G. (1994). Alzheimer disease:
an imbalance of proteolytic regulation? Med. Hypotheses 42, 277-279.
Smith, M. A., Taneda, S., Richey, P. L., Miyata,
S., Yan, S.-D., Stern, D., Sayre, L. M., Monnier, V. M. and Perry, G. (1994a).
Advanced Maillard reaction products are associated with Alzheimer disease
pathology. Proc. Natl. Acad. Sci. USA 91, 5710-5714.
Smith, M. A., Kutty, R. K., Richey, P. L., Yan,
S.-D., Stern, D., Chader, G. J., Wiggert, B., Petersen, R. B. and Perry,
G. (1994b). Heme oxygenase-1 is associated with the neurofibrillary pathology
of Alzheimer's disease. Am. J. Pathol. 145, 42-47.
Smith, M. A., Sayre, L. M., Monnier, V. M. and
Perry, G. (1995a). Radical AGEing in Alzheimer's disease. Trends Neurosci.
Smith, M. A., Rudnicka-Nawrot, M., Richey, P.
L., Praprotnik, D., Mulvihill, P., Miller, C. A., Sayre, L. M. and Perry,
G. (1995b). Carbonyl-related posttranslational modification of neurofilament
protein in the neurofibrillary pathology of Alzheimer's disease. J. Neurochem.
Smith, M. A., Sayre, L. M., Vitek, M. P., Monnier,
V. M. and Perry, G. (1995c). Early AGEing and Alzheimer's. Nature 374,
Smith, M. A., Perry, G., Richey, P. L., Sayre,
L. M., Anderson, V. E., Beal, M. F. and Kowall, N. (1996a). Oxidative damage
in Alzheimer's. Nature 382, 120-121.
Smith, M. A., Siedlak, S. L., Richey, P. L., Nagaraj,
R. H., Elhammer, A. and Perry, G. (1996b). Quantitative solubilization
and analysis of insoluble paired helical filaments from Alzheimer disease.
Brain Res. 717, 99-108.
Smith, M.A., Harris, P.L.R., Sayre, L.M. and Perry,
G. (1997a). Iron accumulation in Alzheimer disease is a source of redox-generated
free radicals. Proc Natl Acad Sci USA 94, in press.
Smith, M. A., Harris, P. L. R., Sayre, L. M.,
Beckman, J. S. and Perry, G. (1997b). Widespread peroxynitrite-mediated
damage in Alzheimer's disease. J. Neurosci. 17, 2653-2657.
Smith, M. A. (1997). Alzheimer Disease. In: International
Review of Neurobiology, R. J. Bradley and R. A. Harris (Eds.). Academic
Press, San Diego. In press.
Sternberger, N. H., Sternberger, L. A. and Ulrich,
J. (1985). Aberrant neurofilament phosphorylation in Alzheimer disease.
Proc. Natl. Acad. Sci. USA 82, 4274-4276.
Stewart, W. F., Kawas, C., Corrada, M. and Metter,
E. J. (1997). Risk of Alzheimer's disease and duration of NSAID use. Neurology
Strittmatter, W. J., Weisgraber, K. H., Huang,
D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D.,
Saunders, A. M., Goldgaber, D. and Roses, A. D. (1993). Binding of human
apolipoprotein E to synthetic amyloid ß peptide: isoform-specific
effects and implications for late-onset Alzheimer disease. Proc. Natl.
Acad. Sci. USA 90, 8098-8102.
Su, J. H., Anderson, A. J., Cummings, B. J. and
Cotman, C. W. (1994). Immunohistochemical evidence for apoptosis in Alzheimers
disease. Neuroreport 5, 2529-2533.
Trojanowski, J. Q., Schmidt, M. L., Shin, R.-W.,
Bramblett, G. T., Goedert, M. and Lee, V. M.-Y. (1993a). PHF-tau (A68):
From pathological marker to potential mediator of neuronal dysfunction
and degeneration in Alzheimer's disease. Clin. Neurosci. 1, 184-191.
Trojanowski, J.Q., Mawal-Dewan, M., Schmidt, M.L.,
Martin, J. and Lee, V.M. (1993b) Localization of the mitogen activated
protein kinase ERK2 in Alzheimers disease neurofibrillary tangles and
senile plaque neurites. Brain Res. 618, 333-337.
Vincent, I., Rosado, M. and Davies, P. (1996).
Mitotic mechanisms in Alzheimer's disease? J. Cell Biol. 132, 413-425.
Vitek, M. P., Bhattacharya, K., Glendening, J.
M., Stopa, E., Vlassara, H., Bucala, R., Manogue, K. and Cerami, A. (1994).
Advanced glycation end products contribute to amyloidosis in Alzheimer
disease. Proc. Natl. Acad. Sci. USA 91, 4766-4770.
Wolozin, B., Iwasaki, K., Vito, P., Ganjei, J.
K., Lacana, E., Sunderland, T., Zhao, B., Kusiak, J. W., Wasco, W., and
D'Adamio, L. (1996). Participation of presenilin 2 in apoptosis: enhanced
basal activity conferred by an Alzheimer mutation. Science 274, 1710-1713.
Yan, S. -D., Chen, X., Schmidt, A. -M., Brett,
J., Godman, G., Zou, Y. -S., Scott, C. W., Caputo, C., Frappier, T., Smith,
M. A., Perry, G., Yen, S. -H., and Stern, D. (1994). Glycated tau protein
in Alzheimer disease: a mechanism for induction of oxidant stress. Proc.
Natl. Acad. Sci. USA 91, 7787-7791.
Yan, S.D., Yan, S.F., Chen, X., Fu, J., Chen,
M., Kuppusamy, P., Smith, M.A., Perry, G., Godman, G.C., Nawroth, P., Zweier,
J.L. and Stern, D. (1995). Non-enzymatically glycated tau in Alzheimer's
disease induces neuronal oxidant stress resulting in cytokine gene expression
and release of amyloid ß-peptide. Nature Medicine 1, 693-699.
Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H.,
Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli,
A., Nawroth, P., Stern, D. and Schmidt, A. M. (1996). RAGE and amyloid-ß
peptide neurotoxicity in Alzheimer's disease. Nature 382, 685-691.
Yankner, B. A., Duffy, L. K. and Kirschner, D.
A. (1990). Neurotrophic and neurotoxic effects of amyloid beta protein:
reversal by tachykinin neuropeptides. Science 250, 279-282.
Zhang, Z., Rydel, R. E., Drzewiecki, G. J., Fuson,
K., Wright, S., Wogulis, M., Audia, J. E., May, P. C. and Hyslop, P. A.
(1996). Amyloid beta-mediated oxidative and metabolic stress in rat cortical
neurons: no direct evidence for a role for H2O2 generation. J. Neurochem.