Volume 6, Number 1, February
2004
Pages
1-9
Alexandre de Mendonça, Filipa Ribeiro, Manuela Guerreiro, Carlos Garcia
Frontotemporal Mild Cognitive Impairment
Abstract: Mild Cognitive Impairment appears to be a heterogeneous
clinical entity comprising patients in the initial phases of distinct
neurological disorders. Since frontotemporal dementia (FTD) is a relatively
common neurodegenerative disease with an insidious onset, it might be
possible to detect the patients in the initial phases of the disorder,
before being demented. In the present work we proposed a set of criteria
to identify patients with mild cognitive impairment of the frontotemporal
type (FT-MCI), applied these criteria retrospectively to a large patient
database, and evaluated the progression of the patients.
Seven subjects fulfilling the proposed criteria for frontotemporal MCI
were identified. They had symptoms of apathy, disinhibition, irritability
and aggressiveness, untidiness, difficulties in decision making, obsessions
and lack of concern for the others, for 1.5±0.8 years before the diagnosis
of FT-MCI. Brain CT or MRI scan displayed fronto-temporal atrophy in five.
Neuropsychological examination revealed deficits in tests dependent upon
the frontal lobe, namely attention, verbal, motor and graphomotor initiatives
and conceptual thinking. The patients kept their professional and daily
activities, and were not demented.
It was possible to have the follow-up of all patients. All but one patient
diagnosed FT-MCI developed dementia of the frontotemporal type within
1.8±1.0 years. Application of the proposed criteria for FT-MCI, at least
in this clinical neurological setting, can identify a group of patients
with a high probability of further cognitive decline to dementia of the
frontotemporal type.
Pages 11-15
J. Riley McCarten, Susan
J. Rottunda, Michael A. Kuskowski (Communicated by James Geddes)
Change in the Mini-Mental State Exam in Alzheimer’s Disease
Over 2 Years: The Experience of a Dementia Clinic
Abstract: The decline in the Mini-Mental State Exam (MMSE)
over 2 years was assessed in males with Alzheimer’s disease (AD;
N=136) seen in a dementia clinic. The average initial MMSE was 21.0
(SD+/-3.9; range 14-29) and declined 2.8 points (+/-4.7; range -17
to +6) over 2 years. The mode for change on the MMSE was 0 (N=22)
while the median fell between 2 and 3 points lost. Fifty-five of 136
patients (39.7%) had unchanged or better scores. There was no
significant correlation between the initial MMSE and rate of change
(r=0.16; p=0.06). While the progression of AD is quite variable from
patient to patient, our data indicate that in most it is associated
with little if any change in the MMSE even over 2 years. The MMSE is
not an adequate tool to monitor change in the individual patient
with AD.
Pages 17-26
A. Bilikiewicz, W.Gaus,
G. Opala, A. Araszkiewicz, I. Kloszewska, L. Bidzan, K. Gustaw, J. Laczkowski,
J. Georgiades
Colostrinin* (a naturally ocurring, proline-rich, polypeptide
mixture) in the treatment of Alzheimer's disease
Abstract: This study was designed to confirm or negate findings from
earlier trials demonstrating that Colostrinin, a novel compound
derived from ewes’ colostrum, has potential in the treatment of mild
or moderate Alzheimer’s Disease (AD). 105 patients were recruited
from six psychiatric centres in Poland. The trial consisted of a 15
week double-blind phase comparing Colostrinin with placebo, followed
by a second 15 week open labelled phase when all patients received
Colostrinin. The dosage of Colostrinin was 100ug on alternate days
for three weeks followed by two weeks drug-free. This cycle was
repeated three times for each phase. The primary outcome measures
used were Alzheimer’s Disease Assessment Scale-cognitive portion (ADAS-cog)
and Clinical Global Impression of Change (CGIC). Secondary outcome
measures were Instrumental Activities of Daily Living (IADL);
Mini-Mental State Examination (MMSE); ADAS-non cognitive test (ADAS-non
cog); and overall Patient Response. The main outcome measures were
assessed at week 15 when active was compared with placebo but all
parameters were evaluated at baseline, week 15 and week 30. Two
separate statistical analyses were undertaken, a Full Sample
Analysis (FSA) in which all missing values were replaced with the
worst result observed and a Valid for Efficacy (VFE) analysis in
which those patients who had serious protocol violations were
excluded. This resulted in 14 patients being excluded from the VFE-analysis.
The FSA analysis at week 15 showed a stabilizing effect of
Colostrinin on cognitive function in ADAS-cog (p = 0.02) and on
daily function in IADL (p = 0.02). The overall patient response was
also in favour of the active (p = 0.03). Patients graded as mild on
entry also showed a superior response of ADAS-cog compared with more
advanced cases (p = 0.01). Evidence from this study indicates an
early beneficial effect on cognitive symptoms and daily function.
Colostrinin has potential value in the treatment AD.
*Colostrinin is the registered trade name for a proline-rich
polypeptide mixture (PRP) derived from ovine colostrum.
Pages 27-30
Daniela Ortiz and Thomas
B. Shea
Apple juice prevents oxidative stress induced by amyloid-beta
in culture
Abstract: Increased oxidative stress contributes to the decline in
cognitive performance during normal aging and in neurodegerative
conditions such as Alzheimer’s disease. Dietary supplementation with
fruits and vegetables that are high in antioxidant potential have in
some cases compensated for oxidative stress. Herein, we examined
whether apple juice could alleviate the neurotoxic consequences of
exposure of cultured neuronal cells to amyloid-ß (Aß), since at
least a portion of the neurotoxicity of Aß is due to oxidative
stress. Apple juice concentrate (AJC; 70 degree brix) was diluted
into culture medium of SH-SY-5Y human neuroblastoma cells that had
been differentiated for 7 days with 5µM retinoic acid concurrent
with the addition of 20µM Abeta. AJC prevented the increased
generation of reactive oxygen species (ROS) normally induced by Aß
treatment under these conditions. AJC also prevented Aß-induced
calcium influx and apoptosis, each of which results in part due to
increased ROS. These findings suggest that the antioxidant potential
of apple products can prevent Aß-induced oxidative damage.
Pages 31-43
Wieslaw K. Dowjat, Izabela
Kuchna, Thomas Wisniewski, Jerzy Wegiel
A Novel Highly Pathogenic Alzheimer Presenilin-1 Mutation in Codon
117 (Pro117Ser): Comparison of Clinical, Neuropathological and Cell
Culture Phenotypes of Pro117Leu and Pro117Ser Mutations
Abstract: A novel presenilin-1 (PS1) mutation (P117S) in an
American pedigree is described. We compare clinical,
neuropathological and cell culture phenotypes produced by this
mutation with another codon 117 mutation that was earlier discovered
by our group in a Polish kindred. Both mutations are associated with
an unusually severe Alzheimer disease (AD) phenotype, with the onset
starting before the third decade of life, rapid disease progression
and acute presentation of clinical symptoms. The severity of
clinical phenotype was closely correlated with the abundance of
pathology: massive deposition of Aß42 in plaques, severe
neurofibrillary degeneration and neuronal loss. When overexpressed
in mouse neuroblastoma N2a cells, both mutations caused loss of an
ability to promote neurite outgrowth and produced an increase in the
ratio of secreted Aß42/40 amyloid peptides. In stably transfected
N2a cell lines only mutant proteins were endoproteolytically cleaved
indicating some dependability of this process on the presence of
mutation. Taken together, our results show that clinical and cell
culture phenotypes produced by these 2 codon 117 mutations are
closely related suggesting that the pathogenic action of PS1 may
involve effect on neurite outgrowth and endoproteolytic cleavage of
the full-length protein. Given the high potency in vivo and in vitro
of both codon 117 mutations, this site of PS1 must be particularly
important for its normal/pathogenic function.
Pages 45-51
Antonella Vitali, Alessandra
Piccini, Roberta Borghi, Pantaleo Fornaro, Mark A. Smith, Sandra L. Siedlak,
Pierluigi Gambetti, Bernardino Ghetti, Massimo Tabaton
Soluble amyloid ß-protein is increased in frontotemporal
dementia with tau gene mutations
Abstract: The relationship between senile plaques and
neurofibrillary tangles, the main pathologic lesions of Alzheimer’s
disease, is not completely understood. We addressed this issue
examining the type and amount of amyloid ß-protein (Aß) associated
with the soluble and insoluble tissue fractions in the frontal
cortex of 8 cases with frontotemporal dementia with parkinsonism
caused by mutations of the Tau gene (FTDP-17), in which the
intracellular accumulation of polymerised tau is definitely the
primary cause of neurodegeneration. As control, we examined 7 cases
with frontotemporal dementia lacking distinctive histopathology (DLDH)
as well as 8 pathologically normal subjects. In all cases the
presence of Aß deposits was ruled out using immunocytochemistry on
sections adjacent to those used for biochemical analysis. ELISA
analysis showed a 2.7 and 2.1 fold (p <0.01) increase of soluble
Aß42 and Aß40 in FTDP-17, compared to normal and DLDH brains, both
of which had comparable levels of Aß species. Furthermore, the
immunoreactivity of the intracellular Aß42 was significantly
increased in cortical neurons of subjects affected with FTDP-17. The
results demonstrate that the aggregation of tau protein produces an
accumulation of Aß, which, however, does not reach the critical
concentration needed for Aß plaques formation.
Pages 53-65
Stephen Howard Pasternak,
John William Callahan, Don Joseph Mahuran (Communicated by Sharon
Moalem)
The Role of the Endosomal/ Lysosomal System in Amyloid-Beta
Production and the Pathophysiology of Alzheimer’s disease:
Reexamining the Spatial Paradox from a Lysosomal Perspective
Abstract: One of the hallmarks of Alzheimer’s disease is
the cerebral deposition of plaques composed of a 37-43 amino acid
Amyloid-beta (Aß) peptide. Aß is produced by the sequential
proteolytic cleavage of an integral-membrane protein, amyloid
ß-protein precursor (AßPP), first by ß-secretase (BACE), and then by
gamma-secretase, a complex containing presenilin and nicastrin.
Although these cleavages were originally documented to occur in the
endosomal/ lysosomal system, other lines of evidence suggest that
the responsible proteins and activity reside in the ER or Golgi.
This lack of intracellular co-localization of enzyme and substrate
has been referred to as the spatial paradox of Alzheimer's disease.
Here we will review the biology of the lysosome and the literature
supporting the endosomal/ lysosomal production of Aß. We will also
examine some of the data supporting Aß production in the
biosynthetic compartments and demonstrate its compatibility with an
endosomal/ lysosomal model. Finally, we will discuss the possible
role of the acidic environment of the lysosome in the amyloidogenic
process, and review the evidence for intracellular amyloidogenesis
preceding amyloid plaque formation.
Pages 67-78
Enrico Ghersi, Pasquale
Vito, Peter Lopez, Mona Abdallah, Luciano D’Adamio
The intracellular localization of Amyloid ß Protein Precursor (AßPP)
Intracellular Domain Associated protein-1 (AIDA-1) is regulated by
AßPP and alternative splicing.
Abstract: The Amyloid-ß Protein Precursor (AßPP) is a
widely expressed transmembrane protein that is extensively processed
in intracellular vesicular compartments and on the cell membrane. As
a result of two sequential proteolytic cleavages, AßPP releases the
Amyloid-ß (Aß) peptide, which accumulates in insoluble plaques in
the brain of patients affected by Alzheimer’s disease (AD). Another
peptide, a C-terminal fragment named AßPP Intracellular Domain
(AID), is generated by AßPP processing and is released
intracellularly. Several functions for AID have been proposed:
pro-apoptotic peptide, regulator of calcium homeostasis, molecule
involved in transcriptional regulation. Many intracellular proteins,
such as Fe65, Jip-1, Shc, Numb and X11a, interact with AID and
modulate its function by different mechanisms. Here we report the
cloning and initial characterization of two isoforms of a novel
protein that we named AID Associated protein-1a (AIDA-1a), AIDA-1b
and AIDA-1bdeltaAnk. We show that AßPP and the AIDA-1 proteins
interact in vitro, in living cells and, endogenously, in
leukemia cell lines. Transfected AIDA-1a, AIDA-1b and
AIDA-1bdeltaAnk localize in different compartments and the
intracellular distribution of AIDA-1a can be modified by
over-expression of AßPP. AIDA-1 proteins are expressed at high
levels in the brain; thus, studying their involvement in AßPP
processing and AID function might give new insights regarding a
possible role for these molecules in normal brain development and in
the pathogenesis of AD.
Pages 79-92
Leann K. Massey, Alex
L. Mah, Diana L. Ford, Jaime Miller, Jing Liang, Howard Doong, Mervyn
J. Monteiro
Overexpression of Ubiquilin Decreases Ubiquitination and
Degradation of Presenilin Proteins
Abstract: Mutations in presenilin proteins (PS1 and PS2) are
associated with most cases of early onset Alzheimer’s disease.
Several proteins appear to regulate accumulation of PS proteins in
cells. One such protein is ubiquilin-1, which increases levels of
coexpressed PS2 protein in a dose-dependent manner. We now report
that overexpression of ubiquilin-2, which is 80% identical to
ubiquilin-1, also increases the levels of coexpressed PS1 and PS2
proteins in cells. To investigate the mechanism by which ubiquilin
proteins increase levels of PS proteins, we examined how
overexpression of ubiquilin-1, which possesses all of the key
signature motifs present in ubiquilin proteins, affects PS2 gene
transcription and PS2 protein turnover and ubiquitination. HeLa
cells overexpressing both PS2 and ubiquilin-1 had PS2 mRNA levels
lower than HeLa cells overexpressing PS2 alone, indicating that
ubiquilin-1 overexpression, in fact, decreases PS2 transcription.
Cells overexpressing ubiquilin-1 and PS2 displayed decreased
turnover of high molecular weight (HMwt) forms of PS2 but not of
full-length PS2 proteins. The reduced turnover of HMwt PS2 proteins
appears to be mediated by the binding of the ubiquitin-associated
domain (UBA) of ubiquilin to ubiquitin chains conjugated onto PS2
proteins. Immunoprecipitation studies indicated that ubiquilin-1
overexpression decreases ubiquitination of coexpressed PS2 proteins,
suggesting that binding of ubiquilin might block ubiquitin-chain
elongation. Consistent with this model, we found that the UBA domain
of ubiquilin-1 binds poly-ubiquitin chains in vitro. In
addition, we show that ubiquilin proteins colocalize with
ubiquitin-immunoreactive structures in cells and that ubiquilin
proteins are present within the inner core of aggresomes, which are
structures associated with accumulation 3 of misfolded proteins in
cells. Our results suggest that ubiquilin proteins play an important
role in regulating PS protein levels in cells.
Pages 93-97 Joseph F. Quinn, Kathleen
S. Montine, Milar Moore, Jason D. Morrow, Jeffrey A. Kaye, Thomas J. Montine
Suppression of longitudinal increase in CSF F2-isoprostanes
in Alzheimer’s Disease
Abstract: We report the first longitudinal analysis of cerebrospinal
fluid (CSF) F2-isoprostanes (IsoPs), quantitative in vivo biomarkers
of lipid peroxidation, in patients with mild Alzheimer’s disease
(AD). CSF F2-IsoPs (i) were significantly increased in patients
followed over one year, (ii) correlated with some clinical indices
of dementia following correction for variation in ventricular
enlargement, and (iii) were significantly lower in patients who used
both a-tocopherol and vitamin C.
Pages 99-105
Transcript of Live Discussion
held at the
Alzheimer Research Forum
Protein Folding and Neurodegeneration: Biophysics to the
Rescue?
Pages 107-108
Book Review: Alzheimer: The Life of the Physician and the Career of
a Disease by Konrad Maurer and Ulrike Maurer. Piper Verlag, München, Germany,
2000, 325pp. Reviewed by Gerald Münch.
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