Current Alzheimer Research - Volume 1, Issue 4, 2004

The amyloid β-peptide (Aβ) plays an early and critical role in the pathogenic cascade leading to Alzheimer's disease (AD). Aβ is typically found in extracellular amyloid plaques that occur in specific brain regions in the AD and Down syndrome brain. Mounting evidence, however, indicates that intraneuronal accumulation of this peptide may also contribute to the cascade of neurodegenerative events that occur in AD and Down syndrome. A pathogenic role for intracellular Aβ is not without precedent, as it is known to be an early and integral component of the human muscle disorder inclusion body myositis (IBM). Therefore, it is plausible that intracellular Aβ may likewise induce cytopathic effects in the CNS, causing neuronal and synaptic dysfunction and perhaps even neuronal loss. Here we review recent evidence supporting a pathogenic role for intracellular Aβ in AD, Down syndrome, and IBM.

Alzheimer's disease (AD) is characterized by two major features: (1) degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in cortex and hippocampus; (2) extracellular protein aggregates containing β-amyloid peptides (Aβ) in these cholinergic target areas. So far, the most effective therapy for AD is to enhance cholinergic transmission. Neuromodulatory functions of the cholinergic system are mainly mediated by muscarinic receptors (mAChRs). It has long been recognized that mAChRs are crucial for the control of high-level cognitive processes. Drugs that activate mAChRs are helpful in ameliorating cognitive deficits of AD. On the other hand, mounting evidence have established detrimental effects of Aβ to cognitive functions. Despite intensive research on AD, it remains unclear how these two prominent features of the disease may be linked to cause cognitive impairments. In this review, we will summarize a series of recent findings on the interactions between cholinergic functions and β-amyloid in normal animals and AD models, and discuss their potential implications in the pathophysiology and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by selective neuronal cell death, which is probably caused by amyloid b-peptide (Aβ) oligomers and fibrils. We have found that acetylcholinesterase (AChE), a senile plaque component, increases amyloid fibril assembly with the formation of highly toxic complexes (Aβ-AChE). The neurotoxic effect induced by Aβ-AChE complexes was higher than that induced by the Aβ peptide alone as shown both in vitro (hippocampal neurons) and in vivo (rats injected with Ab peptide in the dorsal hippocampus). Interestingly, treatment with Aβ-AChE complexes decreases the cytoplasmic β-catenin level, a key component of Wnt signaling. Conversely, the activation of this signaling pathway by Wnt-3a promotes neuronal survival and rescues changes in Wnt components (activation or subcellular localization). Moreover Frzb-1, a Wnt antagonist reverses the Wnt-3a neuroprotection effect against Aβ neurotoxicity. Compounds that mimic the Wnt signaling or modulate the cross-talking with this pathway could be used as neuroprotective agents for therapeutic strategies in AD patients.

Abnormalities in tau modification and tau aggregation are a characteristic histopathological hallmark of Alzheimer's disease (AD). However it is less clear, how tau pathology is linked to other factors, e.g. the formation of amyloid plaques, mutations in the presenilin gene, or the ApoE genotype that all have been shown to contribute to the disease. In this article, data reporting tau's interactions with other factors that may be relevant for AD and that have been obtained from various types of in vitro experiments, cell culture experiments and animal models are summarized and brought into a mechanistic framework. Evidences for functional links of these interactions to neurodegenerative events characteristic for AD are discussed and weighed.

It has been suggested that a high serum cholesterol level is a risk factor for Alzheimer's disease (AD), that treatment with cholesterol-lowering drugs (statins) reduces the frequency of AD development, and that the polymorpholism of genes encoding proteins regulating cholesterol metabolism is associated with the frequency of AD development. However, the mechanism by which high serum cholesterol level leads to AD, still remains unclarified. Several recent studies have shown the results challenging the above notions. Here another notion is proposed, that is, a low high-density lipoprotein (HDL) level in serum and cerebro-spinal fluid (CSF) is a risk factor for the development of AD; moreover, the possibility that AD and Niemann-Pick type C disease share a common cascade, by which altered cholesterol metabolism leads to neurodegeneration (tauopathy) is discussed. In this review, the association between cholesterol and AD pathogenesis is discussed from different viewpoints and several basic issues are delineated and addressed to fully understand the mechanisms underlying this relationship.

Neurodegenerative processes associated with Alzheimer's disease are complex and involve many CNS tissue types, structures and biochemical processes. Factors believed involved in these processes are generation of Reactive Oxygen Species (ROS), associated inflammatory responses, and the bio-molecular and genetic damage they produce. Since oxidative processes are essential to energy production, and to other biological functions, such as cell signaling, the process is not one of risk exposure, as for cigarettes and cancer, but one where normal physiological processes operate out of normal ranges and without adequate control. Thus, it is necessary to study the ambiphilicity that allows the same molecule (e.g., β amyloid) to behave in contradictory ways depending upon the physiological microenvironment. To determine ways to study this in human populations we review evidence on the effects of an exogenous generator of ROS, ionizing radiation, in major population events with radionuclides (e.g., Hiroshima and Nagasaki; Chernobyl Reactor accident; environmental contamination in Chelyabinsk (South Urals) where plutonium was produced, and in the nuclear weapons test area in Semipalatinsk, Kazakhstan). The age evolution, and traits, of neurodegenerative processes in human populations in these areas, may help us understand how IR affects the CNS. After reviewing human population evidence, we propose a model of neurodegeneration based upon the complexity of CNS functions.

Alzheimer's disease (AD) is a common cause of dementia, resulting from accumulated β-amyloid protein deposits in the brain. As the population ages the incidence of AD is also on the rise. The incidence is very high in the developed countries where life expectancy is high, but it is also rising rapidly in the developing countries. Caring for patients suffering from AD is a major economic burden. The mechanisms underlying the neuropathology of AD are slowly being unravelled. Here we explore the many models and theories, which have been proposed over the years. We then discuss a potential therapeutic agent, vaccinia virus complement control protein (VCP), involved in modulating the complement system in AD. VCP has been shown in in vitro studies to block the complement activation caused by the beta peptide. Traumatic injuries to the brain are well known risk factors associated with the development of AD. VCP can also enhance functional recovery resulting from traumatic brain injury and may be able to slow the progression of traumatic brain injury to AD. Here we describe strategies for testing this hypothesis and evaluating other agents such as VCP.

The diagnosis of Alzheimer's disease (AD) is mainly performed by excluding other disorders with similar clinical features. In addition, an analysis of symptoms and signs, blood studies and brain imaging are major ingredients of the clinical diagnostic work-up. However, the diagnosis based on these instruments is unsatisfactory, indicating the need of a highly sensitive and realiable approaches, selective for AD and based on biological markers. Ideally, such markers should reflect the pathophysiological mechanisms of AD, which according to the current hypotheses, derive from the actions of two major protein aggregates, the extracellular β-amyloid (Aβ) plaques and the neurofibrillary tangles. Since AD is a multifactorial disease, other factors that cause neuronal insult and that contribute to neuronal degeneration in AD include free radical and oxidative stress promoting molecules, proinflammatory cytokines and neurotoxic agents. In this context, the search for anomalous levels or changes in the molecular patterns of Aβ(1-42) or Aβ(1-40), hyperphosphorylated tau isoforms, oxidation products in the cell or cytokines such as interleukin-1 or 6 facilitates the selection of biomarkers in AD. There is clear evidence that the cerebrospinal fluid (CSF) levels of Aβ(1-42) are significantly reduced in AD patients as compared with senile controls, while increased levels of tau have been revealed. The CSF levels of these proteins reflect their metabolism in the central nervous system. Approaches using ELISA and immunochemical methods for the quantification of these markers in CSF have been preferentially used. Diagnosis criteria and number of patients exhibits variations in the different reports, while clinico-pathological studies are scarce. An increasing number of studies suggest that supplementary use of these CSF markers preferably in combination, adds to the accuracy of an AD diagnosis.

In this review, the basic mechanism of the parasympathetic nervous effect on the heart is discussed. This is expanded to clinical situations to clarify what can happen to patients after cholinesterase (ChE) inhibitor is administered and to avoid unnecessary adverse effects. The parasympathetic nervous system can affect heart as well as brain function, and its effect on the heart is more complicated than is generally thought. The best-known effect is the cardioinhibitory effect, i.e. slowing of the heart rate. Its effect is also very sensitive to the time at which the stimulus falls within the cardiac cycle (phase-dependent effect). On some occasions, a cardiostimulatory effect can be observed. The parasympathetic nervous system also interacts with the sympathetic nervous system (sympathetic-parasympathetic interaction). ChE inhibitors or acetylcholinesterase inhibitors are often being administered to improve cognitive function of patients with Alzheimer's disease. The heart is naturally rich with ChE, and its inhibition may affect cardiac function, especially in elderly patients, many of whom have concomitant cardiovascular disease. Inhibition of ChE retards ACh degradation and potentiates the cardioinhibitory effect. However, the effect of ChE inhibitor is only slight in patients that receive a typical dose. After administration of ChE inhibitor in humans, the phase-dependent effect is reduced because the parasympathetic nervous effect is potentiated and saturated (saturation mechanism). Beat-by-beat fluctuation is reduced. ChE inhibitor increases arterial blood pressure through central M1 and M2 subtypes of muscarinic receptors (Br J Pharmacol 127:1657-1665, 1999). However, diastolic blood pressure increases slightly.

Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD. This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms. Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups. Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials.