Current Drug Targets - Volume 5, Issue 6, 2004

Neurofibrillary degeneration (ND) is both a pivotal and a primary lesion of Alzheimer disease (AD) and related tauopathies. To date in all known tauopathies including AD, the neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau, and the number of these lesions directly correlates to the degree of dementia in the affected individuals. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAP1 and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF / SF. Missense mutations in tau that cosegregate with the disease in inherited cases of frontotemporal dementia make it a more favorable substrate for hyperphosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. The abnormal hyperphosphorylation of tau and neurofibrillary degeneration may be inhibited by increasing the activity of PP-2A, inhibiting the activity of one or more tau kinases or by the sequestration of normal tau by the abnormally hyperphosphorylated tau. A great advantage of developing therapeutic drugs to inhibit neurofibrillary degeneration is that the efficacy of these drugs can be monitored by assaying the CSF levels of phosphotau and total tau, both of which are elevated in AD. Thus, the development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to AD and related tauopathies.

Alzheimer's disease (AD) is characterized histopathologically by β-amyloid-containing plaques, neurofibrillary tangles (NFT), reduced synaptic density, and neuronal loss in selected brain areas. Plaques consist of aggregates of a small peptide termed Aβ which is derived by proteolysis of the larger amyloid precursor protein APP, whereas NFT are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Tau pathology in the presence of scant or no β-amyloid plaques characterizes additional neurodegenerative disorders collectively called tauopathies. In the course of plaque and NFT formation, the major proteinaceous components of these lesions undergo posttranslational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). This review aims to provide insight into the complexity of tau modifications in human tauopathies such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Selected aspects of the posttranslational modification of tau have been reproduced in transgenic animal models. Most of this work has been done in mice, but insight has also been gained from studies in the sea lamprey, the nematode C. elegans and Drosophila. Attempts have been made to link specific post-translational modifications with tau aggregation and nerve cell dysfunction.

Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Aβ) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1 / 2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the ε4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

Inflammation has been reported in numerous neurodegenerative disorders such as Parkinson's disease, stroke and Alzheimer's disease (AD). In AD, the inflammatory response is mainly located to the vicinity of amyloid plaques. Cytokines, such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α) and Transforming Growth Factor beta (TGF-β) have been clearly involved in this inflammatory process. Although their expression is induced by the presence of amyloid-beta peptide, these cytokines are also able to promote the accumulation of amyloidbeta peptide. Altogether, IL-1, IL-6, TNF-α and TGF-β should be considered as key players of a vicious circle leading to the progression of the disease.

Alzheimer's disease (AD) has become linked to inflammation and metal biology. Metals (copper, zinc and iron) and inflammatory cytokines are significant factors that increase the onset of sporadic late onset forms of the dementia. The genetic discovery that alleles in the hemochromatosis gene accelerate the onset of disease by five years [1] has certainly validated interest in the metallobiology of AD as originally described by biochemical criteria [2]. Also the presence of an Iron-Responsive Element (IRE) in the 5'UTR of the Amyloid Precursor Protein transcript (APP 5'UTR) [3] provided the first molecular biological support for the current model that APP of AD is a metaloprotein. At the biochemical level, copper, zinc and iron were shown to accelerate the aggregation of the Aβ peptide and enhance metal catalyzed oxidative stress associated with amyloid plaque formation [4]. These amyloid associated events remain the central pathological hallmark of AD in the brain cortex region of AD patients. The involvement of metals in the plaque of AD patients and the demonstration of metal dependent translation of APP mRNA have encouraged the development of chelators as a major new therapeutic strategy for the treatment of AD, running parallel to the development of a vaccine. The other notable pathological feature of AD discussed here is inflammation. The presence of neuro-inflammatory events during AD was supported by clinical trials wherein use of non steroidal anti-inflammatory drugs (NSAIDs) was shown to reduce the risk of developing AD. Drug targets that address inflammation include the use of small molecules that prevent Aβ peptide from activating microglia, the use of cytokine suppressive anti-inflammatory drugs (CSAIDS), and the continued search for a vaccine directed to Aβ sub-fragments (even though the full-length Aβ immunogen generated braininflammation and encephalitis in some patients). Our laboratory currently uses a transfection-based assay to screen for small molecule drugs that selectively suppress the capacity of the APP 5'UTR to confer expression to a downstream reporter gene. Based on the presence of both an Interleukin-1 (IL-1) responsive acute box domain and an IRE in the APP 5'UTR, we predict that our APP 5'UTR directed drug screens will identify both novel metal chelators and novel NSAIDS. These lead drugs are readily testable to measure APP holoprotein expression in a cell based secondary assay, and by use of an APP transgenic mouse model to test potential beneficial effects of lead drug treatments on amyloid burden.

A growing wealth of evidence indicates that the key pathological event in Alzheimer's disease is the conversion of the normal soluble amyloid-β peptide into β-sheet-rich oligomeric structures which have a neurotoxic activity and ability to form insoluble amyloid deposits that accumulate in the brain. b-sheet breakers constitute a new class of drugs that are designed to specifically bind amyloid-β peptide and block and / or reverse this abnormal conformational change. In this article we review this approach, describe diverse compounds reported to have this activity and summarize the data supporting the view that b-sheet breakers could be serious candidates to combat this devastating disease.

In this review, we discuss the role of cell cycle dysfunction in the pathogenesis of Alzheimer disease and propose that such mitotic catastrophe, as one of the earliest events in neuronal degeneration, may, in fact, be sufficient to initiate the neurodegenerative cascade. The question as to what molecule initiates cell cycle dysfunction is now beginning to become understood and, in this regard, the gender-predication, age-related penetrance and regional susceptibility of specific neuronal populations led us to consider luteinizing hormone as a key mediator of the abnormal mitotic process. As such, agents targeted toward luteinizing hormone or downstream sequelae may be of great therapeutic value in the treatment of Alzheimer disease.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet β-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-β peptide (Aβ) in mouse brain and to reduce levels of β-amyloid precursor protein (βAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steadystate conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone / 9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be an useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

The inflammatory response of the lung and airways is one of the main targets for the development of new therapies for variety of disorders including the acute respiratory distress syndrome, cystic fibrosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Over the last decade our understanding of the molecular biology of the inflammatory response has advanced considerably and has opened up new avenues for therapeutic intervention. Furthermore, the mechanism of action of many of the existing anti-inflammatory agents has been revealed by this burgeoning information. Here, we discuss the functions and therapeutic potential of molecules that might prove promising as targets for treatment of inflammatory lung diseases. These possible molecular targets include cell surface proteins / receptors [toll like receptors (TLRs), triggering receptors expressed on myeloid cells (TREMs), and syndecans)], transcription factors [NF-κB, AP-1, PU.1, and high mobility group box 1 (HMGB1)], and regulatory proteins [macrophage migration inhibitory factor (MIF), granulocyte macrophage colony stimulating factor (GM-CSF), cyclooxygenase 2 (COX-2), heme oxygenase 1 (HO-1)].