Current Alzheimer Research - Volume 1, Issue 2, 2004

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-coupledreceptors 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.

Conformational changes of Alzheimer's β-amyloid protein (AβP) 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 β-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 AβP and other disease-related proteins. The roles of membrane lipids and potential development of preventive agents are also discussed.

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.

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 copperinduced 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 M ± 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.

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.

It has been shown in vitro that β-amyloid (Aβ) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that Aβ 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 Aβ in normal aging and particularly in Alzheimer's disease (AD). As we were interested in the early pathogenesis of Aβ 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 Aβ were never colocalized, i.e., vessels with high P-gp expression showed no Aβ deposition in their walls, and vice versa. Aβ deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of Aβ. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase Aβ 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 Aβ 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 Aβ clearance could lead to the accumulation and earlier deposition of Aβ, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.

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, ≥ 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.

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.

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 μl 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 IPtreated 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.