| Volume 5, Number
2, April 2003
Pages 65-77
Francisco García-Sierra, Nupur Ghoshal, Bruce Quinn, Robert W.
Berry, Lester I. Binder
Conformational changes and truncation of tau protein during
tangle evolution in Alzheimer's disease
Abstract: The conformation-dependent antibodies Tau-66 and
Alz-50 recognize discontinuous epitopes on the tau molecule
(residues 155-244 & 305-314 and 5-15 & 312-322, respectively),
thereby defining two distinct conformations. In double- and
triple-label immunofluorescence experiments we discovered that
specific populations of neurofibrillary tangles display either the
Alz-50 or the Tau-66 conformation, but not both. In combination with
other antibodies to several domains of the molecule we demonstrate
that the conformation recognized by Alz-50 seems to be an early
event in the formation of neurofibrillary tangles. This conformation
is characterized by the presence of predominantly intact N- and C-
termini. By contrast, the Tau-66 conformation is likely a later
event in tangle development, being favored in structures containing
truncations of both the N- and C- termini. We propose a sequence of
events that occurs during the formation and evolution of
neurofibrillary tangles based on the initial conformation adopted by
tau. In this scheme, the Tau-66 conformation in neurofibrillary
tangles may arise from amino and carboxy truncation of tau after it
has assumed the Alz-50 conformation. These results indicate that tau
structure within the NFT is dynamic in that tau can undergo a
“refolding” event following N- and C-terminal truncation.
Commentary on the García-Sierra et
al. manuscript:
Pages 79-80
Boon-Seng Wong, Matthew Whiteman
Catching tau in the act
Pages 81-90
D.K. Lahiri, D. Chen, D. Vivien, Y.-W. Ge, N.H. Greig, J. T. Rogers
Role of cytokines in the gene expression of amyloid
ß-protein precursor: identification of a 5'-UTR-binding nuclear
factor and its implications in Alzheimer’s disease
Abstract: One of the major neuropathological
characteristics of Alzheimer’s disease (AD) is the brain depositions
of senile plaques that are mainly composed of toxic amyloid
ß-peptide (Aß), which is generated from a family of Aß containing
precursor proteins (AßPP; 695-770 amino acids). The role of
cytokines and growth factors has been implicated in the pathogenesis
of AD. Our goal is to determine the mode of action of cytokines on
the regulation of AßPP gene expression. Here we studied the effect
of different cytokines on the activity of 5'-untranslated region
(5'-UTR) of AßPP mRNA in human astrocytic cells (U-373). We compared
AßPP-5'-UTR activity in the presence of interleukin-1 (IL-1alpha and
IL-1ß), transforming growth factor (TGF-ß1) and tumor necrosis
factor TNF-alpha1. The astrocytic cells, which were treated
separately with these agents, were transfected with either the
vector (pSV2CAT) or pSV2UTR-CAT construct containing 90 bp of AßPP
5'-UTR (+54 to 144 bp). This region was cloned upstream of a
reporter chloramphenicol acetyl transferase gene (CAT). Our results
indicate that the treatment of pSV2UTR-CAT-transfected cells with
either IL-1alpha, IL-1ß, TGF-ß1 or TNF-alpha1 stimulated reporter
gene activity in a factor-specific manner. This was consistent with
their effects on elevating AßPP protein levels. Transfection of the
same cells with the pSV2CAT vector lacking 5'-UTR resulted in a
reduced reporter gene activity with all treatments studied. DNA-gel
shift experiments indicate that the 54/144 region binds to a nuclear
protein(s) in a cell type specific manner. These results suggest
that 5'-UTR of the AßPP gene can respond to the stimulation of
different cytokines, which likely regulate AßPP transcription and
translation via regulatory elements present in the APP promoter and
in 5'-UTR, respectively. The characterization of AßPP regulatory
elements, including the 5'-UTR, will accelerate the development of
novel agents against new targets for AD.
Pages 91-104
Jonas I. Addae, Farid F. Youssef, Trevor W. Stone
Neuroprotective role of learning in dementia: a biological
explanation
Abstract: Several epidemiological studies have found an
association between low educational level (or low cognitively
demanding occupations) and dementia. Although other studies have not
found evidence to support such an association, there has been a
general trend toward a “use it or lose it” concept which attempts to
promote a neuroprotective role of intellectual activity against the
development of dementia. Formation of ß-amyloid peptide (Aß) in the
brain plays a key role in the development of Alzheimer’s disease
whilst glutamate has been implicated in the pathophysiology of a
number of neurological disorders including Alzheimer’s disease and
vascular dementia. Aß can mediate neurodegeneration by a complex
interaction of neurodegenerative processes that involve increasing
extracellular concentration of glutamate, increasing intracellular
Ca2+ concentration, and apoptosis. Long-term potentiation (LTP, a
biological correlate of learning and memory) increases the
sensitivity of hippocampal neurons to synaptically released
glutamate whilst decreasing responses of neurons to bath applied
glutamate receptor agonists and to hypoxia/ischemia in vitro. The
effects of LTP are likely to involve changes in intracellular Ca2+
concentration. Based on these findings we are proposing that the LTP-induced
neuroprotection in vitro may help explain the epidemiological
evidence of a possible neuroprotective role of high intellectual
activity against dementia.
Pages 105-117
Ann Marie Szczepanik, Garth E. Ringheim
IL-10 and Glucocorticoids Inhibit Aß(1-42)- and
Lipopolysaccharide-Induced Pro-Inflammatory Cytokine and Chemokine
Induction in the Central Nervous System
Abstract: Alzheimer's disease (AD) is characterized by
neuropil threads composed of structurally abnormal neurites, neurons
containing paired helical filaments of tau protein, and
extracellular deposits of ß-amyloid (Aß) peptide, a protein fragment
having neurotoxic and glial immune response activating potential. In
the present study, we demonstrate that an acute
intracerebroventricular (icv) injection of Aß(1-42) in the mouse
induces a time- and dose-dependent production of IL-1alpha, IL-1ß,
IL-6 and MCP-1 in the hippocampus and cortex as measured by ELISA.
Cytokine and chemokine levels were maximal at 9 h, with MCP-1 and
IL-1alpha remaining elevated over a 24 h period and IL-1ß remaining
elevated over a 48 h period. The temporal profile of Aß-induced
cytokine induction differed from that observed for LPS. Following an
icv injection of LPS, maximal levels of IL-1alpha, IL-1ß, IL-6 and
MCP-1 were attained by 9 h and, except for MCP-1, returned to levels
indistinguishable from control at 24 h. MCP-1 remained elevated at
24 h and returned to basal levels at 48 h. In contrast, little
production of TNF-a was observed under either Aß or LPS acute
stimulus conditions. Treatment with anti-inflammatory agents such as
prednisolone, dexamethasone, or IL-10 inhibited both Aß- and
LPS-induced cytokine and chemokine production in the brain. In
summary, icv administration of Aß and LPS induced elevated brain
levels of pro-inflammatory cytokines that could be inhibited by
immune suppressing drugs and anti-inflammatory proteins, thus
providing support for the utility of anti-inflammatory therapeutics
in modulating the immunopathology observed in brain inflammatory
diseases such as AD.
Pages 119-125
Annette Skræp Nielsen, Rivka Ravid, Wouter Kamphorst, Ole Steen
Jørgensen
Apolipoprotein E e4 in an autopsy series of various
dementing disorders
Abstract: Apolipoprotein E (APOE) allele e4 is a risk
factor for Alzheimer’s disease (AD) and has also been associated
with impaired recovery from brain injury. Previous studies on APOE
e4 in dementing disorders other than AD have been rather
conflicting, in particular concerning frontotemporal dementia (FTD)
and vascular dementia (VD). In the present study we determined APOE
genotype in an autopsy series of demented subjects and non-demented
controls from the Netherlands Brain Bank. We attempted to create as
clear-cut diagnostic groups as possible and paid close attention to
AD-type histopathological changes in all cases. In comparison with
the APOE e4 allele frequency in controls (0.12; n=163 subjects), the
APOE e4 allele frequency was significantly increased in AD (0.42;
n=320, p<0.0001), as well as in AD with Lewy bodies (0.43; n=41,
p<0.0001) and in demented subjects with no other neuropathological
findings than AD-histopathology insufficient for a diagnosis of AD
(0.29; n=41, p<0.001). However, the APOE e4 allele frequency was not
significantly increased in FTD (0.18; n=49), VD (0.10; n=20) or in
Lewy body disease without concomitant AD changes (0.13; n=12). As
concerns dementing disorders, our results suggest that APOE e4 is
selectively associated with the presence of AD-type histopathology.
Pages 127-137
Ming-Sum Lee and Li-Huei Tsai (Communicated by
James Geddes)
Cdk5: one of the links between senile plaques and neurofibrillary
tangles?
Abstract: The relationship between amyloid plaques and
neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's
disease (AD), is an unknown and controversial subject. However,
emerging evidence from genetic and biochemical studies suggests that
accumulation of amyloid ß peptides may play a causative role in AD
pathogenesis. This led to the amyloid hypothesis, which proposes
that amyloid ß peptides disrupt neuronal metabolic and ionic
homeostasis and cause aberrant activation of kinases and/or
inhibition of phosphatases. The resulting alteration in kinase and
phosphatase activities ultimately leads to hyperphosphorylation of
tau and formation of neurofibrillary tangles. Cyclin-dependent
kinase 5 (Cdk5) is a tau kinase whose activity is induced by amyloid
ß peptides. Its deregulation may represent one of the signal
transduction pathways that connect amyloid ß toxicity to tau
hyperphosphorylation. This article reviews the functions and
regulation of Cdk5. Evidence that suggests deregulation of Cdk5
activity in AD by virtue of calpain cleavage of its activator p35 to
p25 will be discussed.
Pages 139-148
Qiu-Lan Ma, Piu Chan, Mitsunobu Yoshii, Kenji Uéda
Alpha-synuclein aggregation and neurodegenerative diseases
Abstract: Alpha-synuclein is a neuronal protein originally
identified in Alzheimer’s disease (AD) amyloid plaques in 1993 and
named non-Aß component precursor (NACP). Later, the discovery of two
missense mutations (G88C and G209A), which resulted in Ala30Pro
(A30P) and Ala53Thr (A53T) substitutions, of the alpha-synuclein
gene in certain autosomal-dominant early onset familial Parkinson's
disease (PD) has greatly promoted the understanding of the role of
alpha-synuclein in the pathogenesis of neurodegenerative diseases,
such as PD, dementia with Lewy bodies (DLB) and multiple system
atrophy (MSA). At present, it is widely accepted that alpha-synuclein
may play a central role in several neurodegenerative disorders
because of the presence of insoluble alpha-synuclein as the major
fibrillar component of inclusion bodies. From the cloning of the
human alpha-synuclein cDNA in 1993 to the present, alpha-synuclein
has been carefully documented in many aspects. In this article, we
review the progress of studies on alpha-synuclein and its role in
alpha-synuclein-related neurodegenerative diseases.
Pages 149-158
Nadia Jahroudi, Alvin Schmaier, Sujata Srikanth, Fakhri Mahdi,
Frances A. Lutka, Robert Bowser
Von Willebrand factor promoter targets the expression of
amyloid precursor protein to brain vascular endothelial cells of
transgenic mice
Abstract: Dysfunction of brain vascular endothelial cells
may be associated with the pathogenesis of several diseases
including cerebral amyloid angiopathy, hemorrhagic stroke and
Alzheimer disease. New model systems are necessary to examine the
contribution of brain endothelial cells in these disorders. The Von
Willebrand factor gene promoter fragment that spans sequences -487
to +247 targets the expression of LacZ marker gene in transgenic
mice specifically to brain vascular endothelial cells. Transgenic
mice have been prepared that express human amyloid ß-precursor
protein (AßPP) isoforms 695 and 751 (wild-type and Dutch variant
mutations) under the regulation of this VWF promoter sequence. These
AßPP transgenes are specifically expressed in brain vascular
endothelial cells. The VWF promoter is a valuable tool for targeting
gene expression to brain vascular endothelial cells to provide a
model to directly examine endothelial cell placement of genes and
their contribution to cerebral vascular disease.
Pages 159-160
Book Review: Research and Practice in Alzheimer’s Disease,
Volume 6. Vellas B, Fitten LJ, Winblad B, Feldman H, Grundman M,
Giacobini E, Kurz A (Eds). Serdi Publisher, Paris, and Springer
Publishing Company, New York, 2002. Reviewed by A. Claudio Cuello
Pages 161-168
Transcript of Live Discussion held at the
Alzheimer Research Forum
Vascular Disease, Parkinson's, And Now Alzheimer's - Is
Homocysteine the New All-Around Bad Guy?
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