Amyloid inhibitors and Alzheimer's disease

Neuritic plaques composed of amyloid beta-protein (A beta) are an early and invariant neuropathological feature of Alzheimer's disease (AD). The current preclinical search for drugs is mainly focused on decreasing A beta production by inhibiting beta- or gamma-secretase, blocking the formation of these plaques by preventing A beta protofibril and fibril formation, and alleviating the toxic effects of neuritic plaque deposition. Increasing numbers of drugs currently used as therapies for other diseases are now entering clinical trials for AD, but the molecular targets of these drugs and their relevance to A beta toxicity needs to be thoroughly addressed. This knowledge will allow us to fully understand the A beta-related pathways in AD pathogenesis and explore novel therapeutic interventions.     

Amyloid forming proteases: therapeutic targets for Alzheimer's disease

Alzheimer's disease is an age-related neurodegenerative disease which causes global loss of cognitive function. Drug treatment for Alzheimer's disease has been limited to agents that ameliorate behavioral symptoms but these agents are without effect on disease progression. Rational drug design for the treatment of Alzheimer's disease now seems possible. As a result of major advances in medical research in this area, knowledge of the etiology of Alzheimer's disease is rapidly being understood. This information has uncovered relevant and novel targets for treatment. At the center of the etiological progression of this disease is beta-amyloid. A substantial body of evidence strongly suggests that this small protein is critical to the development of Alzheimer's disease. The beta-amyloid protein is generated by two different proteolytic cleavages. Recently, the proteases responsible for producing the beta-amyloid protein have been identified. The proteases represent viable targets for therapeutic intervention against Alzheimer's disease. In this review, we describe the biological characteristics of the beta-amyloid-forming proteases in the context of pharmaceutical development.     

Amyloid cascade hypothesis of Alzheimer's disease and alpha 7 nicotinic receptor]

It is known that beta amyloid protein (A beta) plays an important role in the pathology of Alzheimer's disease (AD). In this review, the role of cellular signaling in the protective action of nicotine for A beta-induced neurotoxicity is described. Recent biochemical and functional studies have demonstrated that A beta interacts directly with the alpha 7 nicotinic receptor, suggesting that A beta might have a function as an endogenous ligand for this receptor. Thus the role of alpha 7 nicotinic receptor in the A beta cascade hypothesis of AD and the possibility of alpha 7 nicotine receptor agonists as the therapeutic drugs for AD are discussed.     

Amyloid deposition as the central event in the aetiology of Alzheimer's disease.

While there may be many causes of Alzheimer's disease (AD), the same pathological sequence of events, described here by John Hardy and David Allsop, is likely to occur in all cases. The recent discovery of a pathogenic mutation in the beta-amyloid precursor protein (APP) gene on chromosome 21 suggests that APP Mismetabolism and beta-amyloid deposition are the primary events in the disease process. The occurrence of AD in Down syndrome is consistent with this hypothesis. The pathological cascade for the disease process is most likely to be: beta-amyloid deposition----tau phosphorylation and tangle formation----neuronal death. The development of a biochemical understanding of this pathological cascade will facilitate rational design of drugs to intervene in this process.     

Amyloid precursor protein,presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing beta-amyloid (A beta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of both familial and sporadic AD have not been fully elucidated. The autosomal-dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding APP, presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). APP is processed by several different proteases such as secretases and/or caspases to yield A beta and carboxyl-terminal fragments, which have been implicated in the pathogenesis of Alzheimer's disease. Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of A beta and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. Recent studies have strongly suggested the possible pathogenic interactions between A beta, presenilins, and/or alpha-synuclein. Therefore, treatments that block the accumulation of A beta and alpha-synuclein might benefit a broad spectrum of neurodegenerative disorders. This review covers the trafficking and processing of APP, amyloid cascade hypothesis in AD pathogenesis, physiological and pathological roles of presenilins, molecular characteristics of alpha-synuclein, their interactions, and therapeutic strategies for AD.     

Amyloid flirting with synaptic failure: towards a comprehensive view of Alzheimer's disease pathogenesis

Many neurological disorders accompanied by cognitive deficits exhibit abnormal synaptic function. This emerging concept is exemplified by Alzheimer's disease. According to the amyloid hypothesis, Alzheimer's disease is thought to be caused by the progressive accumulation and deposition of neurotoxic Amyloid beta-peptide in amyloid plaques and aggregates in brain. Now new theories are emerging associating synaptic and neuronal loss to Amyloid beta monomers and Amyloid beta oligomers. In particular, Amyloid beta oligomers have been described as the earliest effectors to adversely affect synaptic structure and plasticity. In this way, they compromise aspects of learning and memory, including long-term potentiation. Local inflammatory changes, neurofibrillary degeneration, and neurotransmitter deficits all contribute to the memory impairment, but available evidence suggests that these alterations develop as a consequence of early Amyloid beta accumulation. Even more recently, different studies have focused on the capability of neuronal activity itself to influence Amyloid Precursor Protein (APP) metabolism. Neuronal activity modulates, in fact, the formation and secretion of Amyloid beta peptides. The identification of both the mechanism through which Amyloid beta can modify neuronal activity and the way by which neuronal activity can alter APP metabolism is becoming more and more important. And the challenge for the future is, therefore, to find the linkage between these two processes.     

Zinc Inhibits Amyloid �� Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells

Zinc released from excited glutamatergic neurons accelerates amyloid β (Aβ) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer''s disease (AD). Zinc can also alter Aβ concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed Aβ production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased Aβ40 and Aβ42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both β- and α-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of Aβ40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of Aβ secretion.     

The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer's disease

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.     

The expression of cell cycle proteins in neurons and its relevance for Alzheimer's disease

Alzheimer's disease is a chronic neurodegenerative disorder characterised by typical pathological hallmarks such as amyloid deposition, neurofibrillary tangles and disturbances in the expression of various cell cycle proteins. A current pathogenetic hypothesis suggests that neurons, forced by external and internal factors, leave the differentiated G(0) phase and re-enter the cell cycle. This process results in neuronal de-differentiation and apoptosis and might contribute to an increased phosphorylation of the tau protein. There are a number of reports, however, describing the expression of cell cycle proteins in rodent or human brain under normal non-disease conditions. This might indicate that cell cycle expression of proteins in neurons is of physiological rather than pathophysiological relevance. Therefore, it needs to be carefully analysed whether the expression of cell cycle regulators such as cyclin-dependent kinases, cyclins or cyclin-dependent kinase inhibitors in neurons is a pathological hallmark that allows to discriminate between normal and disease condition. Here we attempt to summarise recent evidence for a dysfunction of cell cycle regulators in Alzheimer's disease, considering the potential functions of these molecules beyond cell cycle regulation.     

Intracellular amyloid beta-protein and its associated molecules in the pathogenesis of Alzheimer's disease

Amyloid beta-protein (Abeta) plays a pivotal role in Alzheimer's disease (AD). Therapeutic strategies inhibiting Abeta aggregation and promoting extracellular Abeta removal are currently advocated. Here, we review recent literature on intracellular Abeta, especially intranuclear Abeta, and its associated molecules. We also discuss alternative therapeutic strategies to inhibit intracellular Abeta-related pathogenesis.     

Patent Evaluation: Transgenic Animals with Alzheimer's Amyloid Precursor Gene

Summary

Novelty: A transgenic rodent is disclosed which may be useful for studying Alzheimer's disease (AD). According to the present invention, a transgenic animal is provided which displays tissue-specific overexpression of a gene which encodes Alzheimer amyloid precursor protein (AAP protein) in the regions of the brain where amyloid deposits are commonly found in patients with AD. The transgenic animals thus provide an in vivo model which possesses a physical condition that closely resembles a pathological condition of patients afflicted with AD.

Biology: The transgenic rodent has a transgene comprising a mammalian metallothionine I (MtI) promoter operably linked to a nucleotide sequence which encodes the Alzheimer amyloid precursor protein (AAP protein) operably linked to a mammalian growth (GH) hormone 3′untranslated region. A recombinant DNA molecule is also provided comprising a mammalian MtI promoter operably linked to a nucleotide sequence which encodes AAP protein operably linked to a mammalian GH 3′-untranslated region.     

Amyloid beta-peptide [1-42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences

In addition to synapse loss, neurofibrillary tangles, and neurodegeneration, oxidative stress and amyloid beta-peptide [Abeta] deposition are hallmarks of Alzheimer's disease [AD] brain. Our laboratory coupled these two characteristics of AD into a comprehensive model to account for the synapse loss and neurodegeneration in AD brain. This model combines much of the extant studies on AD and is based on oxidative stress associated with amyloid beta-peptide. This review presents evidence in support of this model and provides insight into the molecular basis of this devastating dementing disorder.     

Cerebrolysin in Alzheimer's disease

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on β-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 β intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.     

Amyloidosis and Alzheimer's disease

Alzheimer's disease (AD) is the most frequent type of amyloidosis in humans and the commonest form of dementia. Extracellular Abeta amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma of AD patients, the cognitive areas being the most severely affected. This review focuses on the potential role of amyloid in the development of neurodegeneration and presents studies of AD and other unrelated inherited dementia syndromes associated with neuronal loss and amyloid deposition in the brain.     

Neuroprotective effect of flupirtine in prion disease

Apoptotic neuronal cell death is a hallmark of prion diseases. The apoptotic process in neuronal cells is thought to be caused by the scrapie prion protein, PrPSc, and can be experimentally induced by its peptide fragment, PrP106-126. This process is a target for potential drugs to combat prion disease or to ameliorate its symptoms. Flupirtine (Katadolon), a pyridine derivative that is in clinical use as a nonopioid analgesic, has a potent cytoprotective effect, at concentrations above 1 microg/mL, on neuronal cells treated with PrP(Sc) or PrP106-126. This drug acts as an N-methyl-D-aspartate (NMDA) antagonist, but does not bind to NMDA receptors. Flupirtine normalizes the level of intracellular glutathione and increases the expression of the antiapoptotic Bcl-2 protein in neuronal cells exposed to prion protein. In view of its favorable pharmacokinetic profile, flupirtine is the first drug to be considered as a potential treatment for Creutzfeldt-Jakob disease, the human form of prion diseases. Clinical trials are underway.     

Production of reactive oxygen species from aggregating proteins implicated in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases

The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neurone disease and the 'prion' dementias. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the beta-amyloid (Abeta), which accumulates in the brain in AD, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown recently that solutions of Abeta liberate readily detectable amounts of hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). We have also obtained similar results with alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, we now support the idea that one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD, PD, and possibly some other protein conformational diseases, could be the direct production of ROS during formation of the abnormal protein aggregates. This hypothesis suggests a novel approach to the therapy of this group of diseases.