Current Alzheimer Research, Vol. 1, No. 2, 2004
Contents
New Insights into
Serotonin 5-HT4 Receptors : A Novel Therapeutic Target for
Alzheimer’s Disease? Pp. 79-85
Marjorie Maillet, Sylvain J.
Robert and Frank Lezoualc’h
Disruption of Calcium
Homeostasis in the Pathogenesis of Alzheimer’s Disease and Other Conformational
Diseases Pp. 87-95
Masahiro Kawahara
Assembly In
Vitro of Tau Protein and its Implications in Alzheimer’s Disease Pp.
97-101
Jesus Avila, Mar Perez, Jose
J. Lucas, Alberto Gomez-Ramos, Ismael Santa Maria, Francisco Moreno, Mark
Smith, George Perry and Felix Hernandez
Increased
Susceptibility to Plasma Lipid Peroxidation in Alzheimer Disease Patients
Pp. 103-109
Carmen Galbusera, Maurizio
Facheris, Fulvio Magni, Gloria Galimberti, Gessica Sala, Lucia Tremolada,
Valeria Isella, Franca Rosa Guerini, Ildebrando Appollonio, Marzia Galli-Kienle
and Carlo Ferrarese
Reactive Oxygen
and Nitrogen Species in Alzheimer’s Disease Pp. 111-119
Mutay Aslan and Tomris Ozben
The Role of
P-glycoprotein in Cerebral Amyloid Angiopathy; Implications for the Early
Pathogenesis of Alzheimer’s Disease Pp. 121-125
Silke Vogelgesang, Rolf W. Warzok, Ingolf Cascorbi, Christiane Kunert-Keil1, Eike Schroeder, Heyo K. Kroemer, Werner Siegmund, Lary C. Walker and Jens Pahnke
Cystathionine Beta
Synthase as a Risk Factor for Alzheimer Disease Pp. 127-133
Katrin Beyer, Jose I. Lao, Cristina Carrato, Ana Rodriguez-Vila, Pilar Latorre, Maria Mataro, Maria A. Llopis, Jose L. Mate, Aurelio Ariza
Neurobiology and
Genetics of Behavioural Syndromes of Alzheimer’s Disease Pp. 135-142
Stephen McIlroy and David Craig
Correlation of
Alzheimer-like Tau Hyperphosphorylation and fMRI Bold Intensity Pp. 143-148
Wang Xiao-Chuan, Hu Zheng-Hui, Fang Zheng-Yu, Feng Yue, Yang Yun-Huang, Wang Qun, Tang Xiao-Wei, Wu Yi-Gen, Wang Jian-Zhi
Abstracts
[Back
to top] New Insights into Serotonin 5-HT4
Receptors : A Novel Therapeutic Target for Alzheimer’s Disease?
Marjorie Maillet, Sylvain J. Robert and Frank Lezoualc’h
The serotonin 5-HT4 receptor mediates many physiological effects in the central nervous system. The recent molecular identification of 5-HT4 receptors and the development of selective 5-HT4 receptor ligands have led to many important new insights into the signalling pathways and the physiological roles of these G protein-coupled-receptors in neurones. With respect to neurodegenerative disorders, it is suggested that 5-HT4 agonists may represent a new avenue for the treatment of Alzheimer’s disease. This mini-review will focus on recent in vitro and in vivo pharmacological and biochemical studies showing the involvement of 5-HT4 receptors in cognitive processes and the amyloid precursor protein processing. The potential use of 5-HT4 agonists for the treatment of AD will be discussed.
[Back
to top] Disruption of Calcium Homeostasis in
the Pathogenesis of Alzheimer’s Disease and Other Conformational Diseases
Masahiro Kawahara
Conformational changes of Alzheimer’s b-amyloid protein (AbP) enhance its neurotoxicity and play important roles in the pathogenesis of Alzheimer’s disease. Recent studies have suggested that a common mechanism is based on diverse “conformational diseases”. They share similarity in their formation of b-sheet containing amyloid fibrils by disease-related proteins and the introduction of apoptotic degeneration. Numerous studies, including our own, have revealed that AbP and several disease-related proteins are capable of directly incorporating into membranes, forming calcium-permeable ion channels, and causing abnormal elevation of intracellular calcium levels. This article reviews the current understanding of the pathology of conformational diseases based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may form the molecular basis of neurotoxicity of AbP and other disease-related proteins. The roles of membrane lipids and potential development of preventive agents are also discussed.
[Back to top] Assembly In Vitro
of Tau Protein and its Implications in Alzheimer’s Disease
Jesus Avila, Mar Perez, Jose J. Lucas, Alberto Gomez-Ramos,
Ismael Santa Maria, Francisco Moreno, Mark Smith, George Perry and Felix
Hernandez
Tau is a microtubule associated protein that is also the main component of the aberrant filaments that form aberrant structures like the neuropil threads or the neurofibrillary tangles, found in the brain of Alzheimer´s disease patients. The assembly of tau aberrant filaments could be reproduced in vitro by using a high concentration of tau protein or, at lower protein concentrations, by adding some compounds like polyanions, fatty acids (and derivates), and others. In this mini-review a descriptive analysis of the different conditions needed for in vitro tau polymerization are summarized.
[Back to
top] Increased
Susceptibility to Plasma Lipid Peroxidation in Alzheimer Disease Patients
Carmen Galbusera, Maurizio Facheris, Fulvio Magni, Gloria
Galimberti, Gessica Sala, Lucia Tremolada, Valeria Isella, Franca Rosa Guerini,
Ildebrando Appollonio, Marzia Galli-Kienle and Carlo Ferrarese
Oxidative stress, linked to Abeta-lipid interactions, plays a pathogenetic role in Alzheimer’s disease. We investigated modifications of lipid peroxidation products in plasma of 52 AD patients, 42 healthy controls and 16 patients with amyotrophic lateral sclerosis, a neurodegenerative disease where oxidative stress also plays a pathogenetic role. Final lipid peroxidation products were measured in plasma by thiobarbituric acid reactive substances (TBARS) assay before and after ex vivo oxidative stress catalysed by copper. There were no significant changes at basal conditions, but after copper-induced oxidation TBARS levels were higher in AD patients (19.0 µM ± 2.2) versus both controls (5.2 µM ± 0.8, p<0.001) and ALS patients (7.6 µM ± 2.1, p<0.01). Stimulated TBARS levels were significantly higher in mild and moderate AD (p<0.0001) with respect to controls, but not in severe AD patients, with a significant inverse correlation between disease severity and lipid peroxidation (p<0.005, r2=0.21). Treatment of a subgroup (13) of mild and moderate AD patients with vitamin C and E for three months decreased plasma lipoperoxidation susceptibility by 60%. Thus, oxidative stress, expressed as ex vivo susceptibility to lipid peroxidation, appears to be an early phenomenon, probably related to AD pathogenetic mechanisms.
[Back
to top] Reactive Oxygen and Nitrogen Species in
Alzheimer’s Disease
Mutay Aslan and Tomris Ozben
Age- related neurodegenerative diseases, especially Alzheimer’s disease (AD), are an important health problem globally. AD is clinically characterized by loss of memory, reasoning and speech. The frequency of the disease reaches to 20-40% in the population over the age of 85. Autopsy findings have indicated the presence of senile plaques and neurofibrillary tangles in the brains of patients with AD. These two lesions can be seen in small numbers during normal aging of the brain but occur in large amounts during AD. Although the initiating causes leading to AD are unknown, oxidative damage appears to play an important role in the slowly progressive neuronal death that is characteristic of AD. Indeed, in addition to the presence of senile plaques and neurofibrillary tangles, postmortem analysis of AD brain has also identified markers of oxidative stress including protein nitrotyrosine, carbonyls in proteins, lipid oxidation products and oxidized DNA bases. This review discusses the role of reactive oxygen and nitrogen species in the pathogenesis of AD and examines the relevance of antioxidant therapy in altering and/or inhibiting neurodegeneration associated with the disease.
[Back
to top] The Role of P-glycoprotein in Cerebral Amyloid
Angiopathy; Implications for the Early Pathogenesis of Alzheimer’s Disease
Silke Vogelgesang, Rolf W. Warzok, Ingolf Cascorbi, Christiane Kunert-Keil, Eike Schroeder, Heyo K. Kroemer, Werner Siegmund, Lary C. Walker and Jens Pahnke
It has been shown in vitro that b-amyloid (Ab) is
transported by P-glycoprotein (P-gp). Previously, we demonstrated that Ab immunoreactivity is significantly elevated
in brain tissue of individuals with low expression of P-gp in vascular
endothelial cells. These findings led us to hypothesize that P-gp might be
involved in the clearance of Ab in normal
aging and particularly in Alzheimer’s disease (AD). As we were interested in
the early pathogenesis of Ab deposition,
we studied the correlation between cerebral amyloid angiopathy (CAA) and P-gp
expression in brain tissue samples from 243 non-demented elderly cases (aged 50
to 91 years). We found that endothelial P-gp and vascular Ab were never colocalized, i.e., vessels with
high P-gp expression showed no Ab deposition
in their walls, and vice versa. Ab deposition
occurred first in arterioles where P-gp expression was primarily low, and
disappeared completely with the accumulation of Ab.
At this early stage, P-gp was upregulated in capillaries, suggesting a
compensatory mechanism to increase Ab clearance
from the brain. Capillaries were usually affected only at later stages of CAA,
at which point P-gp was lost even in these vessels. We hypothesize that Ab clearance may be altered in individuals
with diminished P-gp expression due, e.g., to genetic or environmental effects
(such as drug administration). The impairment of Ab clearance could lead to the accumulation and earlier
deposition of Ab, both in the walls of
blood vessels and in the brain parenchyma, thus elevating the risk of CAA and
AD.
[Back
to top] Cystathionine Beta Synthase as a Risk Factor
for Alzheimer Disease
Katrin Beyer, Jose I. Lao, Cristina Carrato, Ana Rodriguez-Vila, Pilar Latorre, Maria Mataro, Maria A. Llopis, Jose L. Mate, Aurelio Ariza
One of the known risk factors for developing Alzheimer disease (AD) is hyperhomocysteinemia. The latter may result from mutations of the genes coding for three key enzymes involved in homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MS], and cystathionine beta-synthase [CBS]). Although MTHFR and MS polymorphisms have been shown to be positively associated with AD in some populations, the relationship of the CBS gene with AD remains undefined.
In order to evaluate whether AD is associated with CBS gene changes leading to decreased CBS activity and homocysteine accumulation, we genotyped the CBS 844ins68 mutation and VNTR polymorphisms of the CBS gene in 206 AD patients and 186 age-matched controls. A slight increase in both 844ins68 mutation and VNTR allele 19 frequencies was detected in the whole AD patient group, compared with controls. The division of AD patients and controls into three age-at-onset/age dependent subgroups (<65 years, 65-74 years, ł 75 years) revealed that the 844ins68 mutation and VNTR allele 19 are independent risk factors for AD development in subjects aged 75 years or more.
[Back
to top] Neurobiology and Genetics of Behavioural
Syndromes of Alzheimer’s Disease
Stephen McIlroy and David Craig
The number of people with cognitive impairment is rising in parallel with changing demographics. As health care budgets are coming under increasing strain with regard to the provision of nursing care, there is a substantial need for effective therapies which encompass greater understanding of the components of dementia that finally necessitate admission to residential or nursing home care. Behavioural and psychological symptoms of dementia (BPSD) are major independent risk factors for admission to institutional care and research into the origin of BPSD is gathering pace. In this review, we evaluate the neurobiological and genetic changes described in individuals with BPSD in Alzheimer’s disease. Particular emphasis is placed on genetic theories of causation, namely that BPSD results directly or indirectly from known genetic risk factors for AD, or distinct genetic risk factors for psychiatric illness assume clinical significance within the degenerated Alzheimer’s brain.
[Back
to top] Correlation of Alzheimer-like Tau
Hyperphosphorylation and fMRI Bold Intensity
Wang Xiao-Chuan, Hu Zheng-Hui, Fang Zheng-Yu, Feng Yue, Yang Yun-Huang, Wang Qun, Tang Xiao-Wei, Wu Yi-Gen, Wang Jian-Zhi
To explore the correlation between cerebral functional alterations revealed by functional magnetic resonance imaging (fMRI) and Alzheimer disease- (AD)-like tau hyperphosphorylation, we injected bilaterally 2 ml each of 20 mM isoproterenol (IP), a PKA activator, or of saline as a vehicle control into the hippocampus of rats. FMRI was employed to measure the intensity of BOLD signal, one of the cerebral functional markers reflecting the changes of cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), in hippocampus and cortex 24 h after the operation. Immunohistochemical staining of hippocampus and cortex was carried out using phosphorylation-dependent tau antibodies. The results showed (1) that BOLD intensity in hippocampus and cortex of IP-injected rats was obviously lower than that of sham-operated group, indicating a decrease in CMRO2 and CBF of the particular brain regions in IP-treated rats; (2) that tau was hyperphosphorylated at Ser-262/Ser-356 (12e8), Ser-396/Ser-404 (PHF-1) sites in CA1 CA2 CA3 CA4 and dentate gyrus regions of hippocampal formation and cortex area in IP group, but not in sham rats; (3) that a negative correlation between tau hyperphosphorylation and BOLD intensity in hippocampus and cortex area of IP rats was observed. The data suggested that hippocampal and cortical tau hyperphosphorylation was intimately related to BOLD intensity of the same areas. To our knowledge, this is the first report exploring the relationship between fMRI BOLD signal and AD-like tau hyperphosphorylation.