Current Pharmaceutical Design - Volume 12, Issue 6, 2006

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 30% of the population over 85 years of age. In 2002, the estimated cost of dementia in Western countries was about 1% of GDP, by 2050, this is expected to increase to about 3%. The development of neuroprotective pharmacological strategies is an important task for the research community. AD is characterized by two characteristic lesions, amyloid plaques and neurofibrillary tangles, which are present in high numbers in the grey matter of affected brain areas. Neurofibrillary tangles are intracellular deposits formed by hyperphosphorylated and extensively crosslinked tau protein. Tau is a microtubule-associated protein that regulates a variety of properties of neuronal microtubules, especially their stability and orientation. In AD, however, tau is hyperphosphorylated and forms fibrillar inclusions. Presumably this leads to neuronal dysfunction by disturbing cytoskeletal functions of neurons, resulting in abnormal axons and therefore impaired axonal transport. Senile plaques are the second characteristic hallmark in AD sufferers. These extracellular protein deposits are mainly composed of beta-amyloid peptide (Aβ) which forms b-sheeted fibrils that become insoluble. Aβ is derived from the β-amyloid precursor protein (APP), an integral membrane protein that is processed by β- and γ-secretases. In a variety of cell culture models, Aβ has been shown to cause toxicity to neurons by various mechanisms, many of which involve oxidative stress. Inflammation, as evidenced by the activation of microglia and astroglia, is another hallmark of AD. Inflammation, including the induction of superoxide production ("oxidative burst"), is an important source of oxidative stress in AD patients. The inflammatory process occurs mainly around the amyloid plaques and is characterized by pro-inflammatory substances released from activated microglia. Reactive oxygen species (ROS) are the most prominent molecules in the inflammatory process, along with prostaglandins, IL-1b, IL-6, M-CSF and TNF-α. In light of the many pathological hallmarks of the disease, selecting a therapeutic target and designing appropriate pharmacological strategies appears to be a very complex and nearly impossible task. This issue of Current Pharmaceutical Design combines contributions from some of the world leaders in the filed of AD therapy and presents a kaleidoscope of theories and approaches, as well as original data mixed with expert reviews. In the first article, Taisuke Tomita and Takeshi Iwatsubo [1] intensively review g-secretase, the pivotal enzyme in generating the C terminus of Aβ. Their manuscript informs the reader on recent progress in g-secretase biology, which has shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme, as well as the recent development of inhibitors of γ-secretase activity.....

Alzheimer's disease (AD) is the most common cause of dementia with aging, that is pathologically characterized by senile plaques that contain amyloid-b peptides (Aβ) and neurofibrillary tangles comprised of phosphorylated tau. Genetic and biological studies provide evidence that the production and deposition of Aβ contribute to the etiology of AD. g-Secretase is the pivotal enzyme in generating the C terminus of Aβ, that determines its aggregability and propensity for deposition. Drugs that regulate the production of Aβ by inhibiting g-secretase activity could provide an effective therapeutics for AD, although recent studies suggest that g-secretase plays important roles in novel signaling pathways that play essential roles in embryonic development. This review focuses on recent progresses in the g-secretase biology that shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme. Moreover, we review the recent development of inhibitors and provide a direction for the effective treatment of AD through inhibition of g-secretase activity.

Considerable effort has been made to develop drugs that delay or prevent neurodegeneration. These include inhibitors of Aβ-generating proteases for the treatment of Alzheimer's disease. Testing the amyloid hypothesis in vivo requires molecules that are capable of entering the CNS and that produce a substantial reduction in brain Aβ levels. Plaque-developing APP transgenic mice are currently widely used as an in vivo model of choice as these animals produce readily measurable amounts of human Aβ. They are very useful in the testing of a variety of amyloid-lowering approaches but their use for compound screening is often limited by their cost. Transgenic animals also require extensive, timeconsuming breeding programs and can show high inter-animal differences in the expression level of the transgene. Hence, we considered it important to develop and characterize a new and simple non-transgenic animal model for testing Aβ modulation. For this purpose, Wild-type adult Sprague Dawley rats were treated with DAPT, a functional γ-secretase inhibitor, and the Aβ40 and Aβ42 levels in brain-tissue and body fluids were assessed. We showed that DAPT, given orally, significantly lowered Aβ40 and Aβ42 peptide levels in brain extract, CSF, and the plasma dose- and timedependently. We can conclude that our data establish the usefulness of the wild-type rat model for testing small-molecule inhibitors of Aβ production.

Although there is still no known effective preventative treatment or cure for Alzheimer's disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Aβ42), the predominant Aβ peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Aβ42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (α7nAChR), and internalization of Aβ42 appears to be facilitated by the high-affinity binding of Aβ42 to the α7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Aβ42 is the dominant Aβ peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Aβ42 binding to α7nAChR on neuronal surfaces that stem from excessive intraneuronal Aβ42 accumulation, the α7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Aβ42 levels in the blood and cerebrospinal fluid as well as blocking Aβ42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.

A significant amount of research has been focused on the relationship between hormones and Alzheimer's disease. However, the majority of this work has been on estrogen and more recently testosterone. A serendipitous patient encounter led one of us (RLB) to question whether other hormones of the hypothalamic-pituitary-gonadal axis could be playing a role in the pathogenesis of Alzheimer's disease. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum luteinizing hormone concentrations. Indeed, there is growing evidence that the gonadotropin, luteinizing hormone, which regulates serum estrogen and testosterone concentrations, could be an important causative factor in the development of Alzheimer's disease. This review provides information supporting the "gonadotropin hypothesis, " puts forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of Alzheimer's disease, and discusses potential therapeutic anti-gonadotropin compounds.

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder with distinct neuropathological features. Extracellular plaques, consisting of aggregated amyloid peptides of 39-43 amino acids are one of the most prominent pathological hallmarks of this disease. Although the exact neurochemical effector mechanism of Aβ aggregation is not yet elucidated, age-associated disturbances of metal ion metabolism have been proposed to promote the formation of aggregates from soluble Aβ. Oxidative stress is postulated to be a downstream effect of Aβ-metal ion interactions. Therefore, the modulation of brain metal metabolism and attenuation of oxidative stress by antioxidant molecules are proposed as a potential therapeutic intervention in AD. Here, we summarize the recent literature focused on APP/Aβ-metal ion interactions and the use of antioxidant metal chelators as potential therapy against AD.

One of the major age-related damaging agents are reactive oxygen species (ROS). The brain is more vulnerable to oxidative stress than other organs as concomitant low activity and capacity of antioxidative protection systems allow for increased exposure of target molecules to ROS. Since neurons are postmitotic cells, they have to live with cellular damage accumulated over many decades. Increased levels of ROS (also termed "oxidative stress"), produced by normal mitochondrial activity, inflammation and excess glutamate levels, are proposed to accelerate neurodegenerative processes characteristic of Alzheimer's disease. This review presents evidence of the importance of oxidative stress in the pathogenesis of these diseases and explains the nature of different types of ROS mediating neuronal damage. Furthermore, the potential beneficial effects of neuroprotective treatments, including antioxidants and anti - glutamatergic drugs are discussed.

Alzheimer's disease (AD) represents one of the most common ailments afflicting the rapidly growing elderly segment of today's population. Despite the vast amount of effort expended in developing a cure, currently approved drugs address only cognitive symptoms that, although important for improving a patient's daily living standard, do not provide a significant delay or halt to disease progression. Early reports that individuals taking anti-inflammatory medications reduce their risk of developing AD has led to the "inflammation hypothesis" of AD and the subsequent testing of these drugs in the clinic. Tests of a select few of these medications in AD clinical trials have, however, yielded disappointing results. Reports of statin-based medications reducing the risk of AD have also led to the testing of this class of drugs in the clinic. Recently, the approval of the NMDA receptor antagonist memantine (Namenda®) has provided clinical support for glutamatergic processes in the disease and generated a renewed interest in the role of excitatory amino acids in the etiology of AD. In this review, we take a closer look at these three compelling areas for addressing AD therapeutics: inflammation, cholesterol, and glutamate. We present arguments that these components are interconnected and mutually regulate processes involved in AD progression. Special focus is given to inflammation as a central feature of AD that may be acting in synergy with cholesterol and glutamate to mediate the observed pathophysiology.

Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca2+ release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.

Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipid mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Δ9-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutic drugs of potential value for the treatment of pathologies in the central nervous system and in the periphery. Here, the potential applications of these inhibitors for human disease will be reviewed, with an emphasis on the properties of hydro(pero)xy-anandamides. In fact, these oxygenated derivatives of AEA are the most powerful inhibitors of FAAH of natural origin as yet discovered. In addition, new insights into the promoter region of FAAH gene will be presented, and the therapeutic potential of mimetics of transcription factors of this gene in the management of human infertility will be discussed.