| Volume 4, Number
5, October 2002
Pages 341-348
Atish Mukerjee and Louis B. Hersh (Communicated by James Geddes)
Regulation of amyloid ß-peptide levels by enzymatic degradation
Abstract: It is generally accepted that amyloid ß peptides
play a significant role in the etiology of Alzheimer’s disease. The
Aß peptides are produced by the sequential cleavage of an amyloid
precursor protein by a ß secretase followed by cleavage by a gamma
secretase. The clearance of the Aß peptides appears to be due
primarily by the action of one or more peptidases. An imbalance
between the rate of synthesis and the rate of clearance of the Aß
peptides is now considered a possible contributor to the onset of
Alzheimer’s disease. This review focuses on peptidases that have
been proposed to contribute to Aß peptide catabolism and discusses
the evidence for their participation in Aß peptide clearance in
vivo.
Pages 349-355
David H. Small and Lisa R. Fodero (Communicated by James Geddes)
Cholinergic regulation of synaptic plasticity as a therapeutic
target in Alzheimer's disease
Abstract: There is increasing evidence for disturbances in
nicotinic acetylcholine receptor (nAChR) function in Alzheimer’s
disease (AD). nAChRs are involved in the regulation of many
processes, including synaptic plasticity and memory. Levels of
nAChRs are altered in the Alzheimer brain and there is evidence that
the amyloid protein (Aß) can directly bind to nAChRs. Nicotinic
agonists may also protect cells from Aß toxicity. Drugs which
interact with the nAChR or which inhibit Aß binding to nAChRs may be
of value for the treatment of AD.
Pages 357-367
Olga V Korchazhkina, Alison E Ashcroft, Tamas Kiss and Christopher
Exley
The degradation of Aß25-35 by the serine protease plasmin is
inhibited by aluminium
Abstract: The catabolism of amyloid beta peptides (Aß) may be
important in their accumulation in the brain in both early and
late-onset Alzheimer’s disease (AD). The serine protease plasmin is
one of a suite of proteases implicated in AD. It is a promoter of
alpha-cleavage of the amyloid ß precursor protein (AßPP) and will
degrade Aß in vitro. Herein we have demonstrated cleavage of
the amyloidogenic Aß25-35 by plasmin to produce the non-amyloidogenic
fragment Aß29-35. The activity of plasmin was halved by pre-mixing
it with aluminium (Al) prior to its addition to the peptide. An
interaction between Al and proteases involved in the catabolism of
Aß might define the putative link between Al and AD.
Pages 369-374
Xie Ling, RN Martins, M Racchi, S Craft, E Helmerhorst
Amyloid beta antagonizes insulin promoted secretion of the
amyloid beta protein precursor
Abstract: Amyloid ß (Aß) peptides are direct competitive
inhibitors of insulin binding and action. We demonstrate that Aß
peptides can inhibit the effect of insulin on the metabolic
processing of the amyloid ß protein precursor (AßPP). As evidence
emerges concerning the role of insulin and insulin like growth
factors (IGFs) in learning and memory, recent findings have
suggested that insulin may have a significant role in the
pathogenetic pathways leading to Alzheimer's disease (AD). As an
example several investigators have demonstrated upregulation of
insulin receptors and defective insulin receptor signal transduction
in AD brains. Moreover insulin has been shown to positively modulate
AßPP proteolytic processing. The fact that insulin and Aß appear to
share a common system for degradation and disposal as they are both
substrates of the insulin degrading enzyme (IDE) suggested the
possibility of a reciprocal interference. Here we report that Aß can
directly interfere with insulin receptor signalling inhibiting the
autophosphorylation of partially purified insulin receptors. As a
consequence of such interaction we also demonstrate that Aß blocks
the effect of insulin on the release of sAßPPalpha in chinese
hamster ovaries (CHO) cells transfected with insulin receptors.
Pages 375-398
Gail V.W. Johnson and Craig D.C. Bailey (Communicated by James
Geddes)
Tau, Where are We Now?
Abstract: Tau is a multifunctional protein that was
originally identified as a microtubule-associated protein. Tau is
primarily a neuronal protein, but it is becoming increasingly
evident that tau is present in non-neuronal cells where it also
plays important roles. Tau is the primary protein component of the
filaments (both paired helical and straight filaments) found in
Alzheimer's disease brain. Further there is an ever growing family
of neurodegenerative diseases called "tauopathies" where tau
pathology is the primary, defining characteristic with little or no
Aß pathology. These findings, along with the fact that mutations in
the tau gene cause a group of diseases collectively known as
frontotemporal dementia with parkinsonism linked to chromosome 17
(FTDP-17), clearly demonstrate that tau dysfunction results in
neuronal dysfunction and death. This review highlights recent
findings concerning the normal metabolism and function of tau, as
well as the abnormal processing and function of tau in Alzheimer's
disease and in the tauopathies, both sporadic and familial.
Pages 399-404
Marina P. Sánchez, Isabel Gonzalo, Jesús Ávila, Justo García de
Yébenes (Communicated by Javier Diaz-Nido)
Progressive supranuclear palsy and tau hyperphosphorylation in a
patient with a C212Y parkin mutation
Abstract: Autosomal recessive-juvenile parkinsonism (AR-JP)
is one of the most common forms of familial Parkinson’s disease (PD)
and is related to mutations in the Park-2 gene, encoding for a
protein ligase of ubiquitin, parkin. Different mutations located
along the parkin gene have been observed in different AR-JP affected
families, possibly interfering with the normal function of parkin
and the proteasome system. Two cases of patients with AR-JP have
been recently described presenting different homo- and heterozygous
parkin mutations and limited tau pathology. We report here the case
of a patient with clinical and pathological findings compatible with
progressive supranuclear palsy (PSP), carrier of a single,
heterozygous mutation of the parkin gene, and homozygous for the
H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation
has been observed in our patient brain samples, suggesting that a
partial deficit of parkin, a protein with ubiquitin-ligase function,
may trigger tau pathology in individuals with molecular genetic risk
factors.
Pages 405-415
Tadanobu Utsuki, Mohammed Shoaib, Harold W. Holloway, Donald K.
Ingram, William C. Wallace,Vahram Haroutunian, Kumar Sambamurti,
Debomoy K. Lahiri, Nigel H. Greig
Nicotine Lowers the Secretion of the Alzheimer’s Amyloid
ß-Protein Precursor that Contains Amyloid ß-Peptide in Rat
Abstract: Reports of an inverse relationship between nicotine
intake, due to cigarette smoking, and the incidence of Alzheimer’s
disease (AD) prompted us to investigate the effects of nicotine on
amyloid ß-protein precursor (AßPP) processing in rat.
Over-production and/or altered metabolism of AßPP, resulting in
increased amyloid ß-peptide (Aß), appear pivotal in the pathogenesis
of AD. Aß is generated proteolytically from AßPP by a group of
secretases. AßPP cleavage by gamma–secretase results in the
secretion of a truncated soluble AßPP (sAPPg) that contains intact
Aß. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette
smoking and a higher but well tolerated dose, respectively, was
administered over 14 days and Western blot analysis was performed on
sAPP fragments. Both doses significantly reduced sAPPg. These
actions were blocked by nicotinic receptor antagonism. Whereas
nicotinic antagonists alone had no effect on either total sAPP or
sAPPg levels in CSF, muscarinic antagonism significantly elevated
them; suggesting that muscarinic rather than nicotinic receptor
silence alters processing of AßPP to favor a potentially
amyloidogenic route. Combined nicotine and muscarinic antagonism
attenuated the action of the latter to elevate sAPPg, indicating
that nicotine modifies AßPP processing away from potentially
amyloidogenic products. These results suggest that within the brain,
levels of total sAPP, sAPPg and, accordingly, Aß are subject to
cholinergic manipulation, offering therapeutic potential at the
level of AßPP processing to decrease Aß deposition.
Pages 417-430
Carola Otth, Ilona I. Concha, Thomas Arendt, Jens Stieler, Reinhard
Schliebs, Christian González-Billault, Ricardo B. Maccioni
AßPP induces cdk5-dependent tau hyperphosphorylation in
transgenic mice Tg2576
Abstract: Previous studies of Aß-induced neuronal damage of
hippocampal cells in culture have provided strong evidence that
deregulation of the Cdk5/p35 kinase system is involved in the
neurodegeneration pathway. Cdk5 inhibitors and antisense probes
neuroprotected hippocampal cells against the neurotoxic action of Aß.
To further investigate the mechanisms underlying the participation
of Cdk5 in neuronal degeneration, the transgenic mouse containing
the Swedish mutations, Tg2576, was used as an animal model.
Immunocytochemical studies using anti-Aß(1-17) antibody evidenced
the presence of labeled small-clustered core plaques in the
hippocampus and cortex of 18-month-old transgenic mice brains. The
loss of granular cells without a compressed appearance was detected
in the vicinity of the cores in the dentate gyrus of the
hippocampus. Immunostaining of Tg2576 brain sections with antibodies
to AT8, PHF1 and GFAP labeled punctuate dystrophic neurites in and
around the amyloid core. Reactive astrocytosis around the plaques in
the hippocampus was also observed. Studies at the molecular level
showed differences in the expression of the truncated Cdk5 activator
p25 in the transgenic animal, as compared with wild type controls.
However no differences in Cdk5 levels were detected, thus
corroborating previous cellular findings. Interestingly,
hyperphosphorylated tau epitopes were substantially increased as
assessed with the AT8 and PHF1 antibodies, in agreement with the
observation of a p25 increase in the transgenic animal. These
observations strongly suggest that the increased exposure of
Alzheimer´s type tau phosphoepitopes in the transgenic mice
correlated with deregulation of Cdk5 leading to an increase in p25
levels. These studies also provide further evidence on the links
between extraneuronal amyloid deposition and tau pathology.
Pages 431-434
Alex E. Roher, Tyler A. Kokjohn
Commentary: Of mice and men: the relevance of transgenic mice
Aß immunizations to Alzheimer’s disease
Introduction: Alzheimer’s disease (AD) is a progressive
neurodegenerative disorder characterized by a time-dependent amyloid
fibril deposition in cortical senile plaques and cerebral vascular
walls. Several transgenic (Tg) mice have been engineered to
overexpress amyloid-beta precursor protein (AßPP) with familial AD
mutations. With advancing age, the Tg mice accumulate amyloid-beta
(Aß) peptides, primarily of 40 to 42 amino acids, in plaques and
blood vessel wall deposits which resemble morphologically those
characteristic of AD. Immunizing Tg mice with Aß peptides or
infusion of anti-Aß antibodies resulted in a remarkable Aß load
decrease and reversal of cognitive dysfunction in these animals.
These observations led to immediate efforts to employ similar
therapeutic protocols in AD patients. However, Tg
hAßPP-overexpressing mice differ from AD patients in several
important biochemical, anatomical, pathological and temporal
aspects. These fundamental differences must be considered when
extrapolating Tg mice Aß vaccination experimental observations to
AD.
Pages 435-445
Transcript of Live Discussion held at the
Alzheimer Research Forum
From Epidemiology to Therapeutic Trials with Anti-Inflammatory
Drugs in Alzheimer’s Disease: The Role of NSAIDs and Cyclooxygenase
in ß-Amyloidosis and Clinical Dementia
RETURN
TO INDEX
top |
|
an IOS Press publication
