Current Alzheimer Research - Volume 7, Issue 2, 2010

Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington’s diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 ≥ 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: α1A (Ki = 55 nM)= ≥1B ≥ α2A (Ki = 120 nM) = α1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki ∼ 600 nM) >D3≥D4.2>D4.4≥D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs.

The hippocampus is critical for learning and memory and heavily affected in dementia. The presence of stem cells in this structure has led to an increased interest in the phenomenon of adult neurogenesis and its role in hippocampal functioning. Not surprising, investigators of Alzheimer's disease have also evaluated adult neurogenesis due to its responsiveness to hippocampal damage. Although causal relationships have not been established, many factors known to impact neurogenesis in the hippocampus, are implicated in the pathogenesis of AD. Also, adult neurogenesis has been proposed to reflect a “neurogenic reserve” that may determine vulnerability to hippocampal dysfunction and neurodegeneration. Since neurogenesis is modifiable, stimulation of this process, or the potential use of stem cells, recruited endogenously or implanted by transplantation, has been speculated as a possible treatment of neurodegenerative disorders. As the structural and molecular mechanisms governing adult neurogenesis are important for evaluating therapeutic strategies, we will here review collective literature findings and speculate about the future of this field with a focus on findings from Alzheimer's mouse models. Continued research in this area and use of these models is critical for evaluating if neurogenesis based therapeutic strategies will indeed have the potential to aid those with degenerative conditions.

The use of natural compounds is an interesting stratagem in the search of drugs with therapeutic potential for the treatment of Alzheimer's disease (AD). We report here the effect of the hyperforin derivative (IDN5706, tetrahydrohyperforin), a semi-synthetic derivative of the St. John's Wort, on the brain neuropathology, learning and memory in a double transgenic (APPswe, PS-1dE9) mouse model of AD. Results indicate that, IDN5706 alleviates memory decline induced by amyloid-β (Aβ) deposits as indicated by the Morris water maze paradigm. Moreover, the analysis of Aβ deposits by immunodetection and thioflavin-S staining of brain sections, only reveals a decrease in the frequency of the largersize Aβ deposits, suggesting that IDN5706 affected the turnover of amyloid plaques. Immunohistochemical analysis, using GFAP and n-Tyrosine indicated that the hyperforin derivative prevents the inflammatory astrocytic reaction and the oxidative damage triggered by high Aβ deposit levels. We conclude that the hyperforin derivative, IDN5706, has therapeutic potential for prevention and treatment of AD.

The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid β-peptide (Aβ). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial α-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by β- and γ- secretase enzymes, which produces Aβ peptides. Currently, the diagnosis of probable or possible Alzheimer's disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet β- secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet α-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of α- and β-secretase in platelets may represent a useful surrogate marker of the balance between the two pathways of APP metabolism and be of importance for the diagnosis of AD. We therefore considered it of interest to develop assays of platelet α- and β-secretase activities suitable for such clinical investigations. Application of these assays to a Swedish population failed to uncover an effect of AD or MCI on individual platelet secretase activities or the secretase ratio. However, we did observe an inverse correlation between plasma triacylglycerol (TAG) levels and the secretase ratio. The results are discussed in the context of the clinical usefulness of the secretase ratio as a biochemical adjunct to the diagnosis of AD.

Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimer's disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Aβ) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Aβ precursor protein (APP), β- or α-secretase pathways, nor with the Aβ catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Aβ formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.

A key event in Alzheimer's disease (AD) pathogenesis is the formation of insoluble peptides β-amyloid aggregates and this process is favoured by a condition of hyperhomocysteinemia. To date, there is growing evidence that implicates glycosaminoglycans (GAGs) in the pathophysiology of amyloidosis but no data are available on the characterization of brain GAGs involved in the enhancing β-amyloid fibrillogenesis in relationship to their structure and physico-chemical properties. Furthermore, few studies have been performed on the relationship between hyperhomocysteinemia and extracellular matrix (ECM) modifications. The aim of this study was to evaluate the amount and chemical structure of GAGs in rat striatal areas where β-amyloid fibrillogenesis was induced, and in conditions of hyperhomocysteinemia. The intrastriatal injection of β-amyloid produced a significant decrease (-40.8%) in the hyaluronic acid (HA) percentage and an increase (+14.5%) in the dermatan sulfate (DS) with a total charge density increasing of 14.9%. A significant decrease (- 19.5%) in the HA percentage and an increase (+6.9%) in the DS % was also observed in striata obtained from the hyperhomocysteinemic animals. The total charge density increased by 6.8%. Quite the same trend was observed in rats after intrastriatal injection of β-amyloid and in a condition of hyperhomocysteinemia. The observed increase of DS concentration and the correspondent decrease of the nonsulfated polymer HA after in vivo treatment with β-amyloid and in a condition of hyperhocysteinemia support the hypothesis that an increase in local production of sulfated GAGs may reduce β- amyloid neurotoxicity. However, the consequent modification of the ECM network might impair the extracellular diffusion pathways of different signal molecules and participate in the progression of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline including loss of memory, orientation and reasoning. However, a relevant aspect of AD is the presence of a variety of behavioural and psychological symptoms in dementia (BPSD), beyond the well-known progressive cognitive impairment. Approximately 50% to 80% of patients diagnosed with AD present behavioural or psychiatric disturbances such as psychosis, depression, agitation, disinhibition, aggression, hyperactivity, and socially intrusive behaviours. These symptoms may be burdensome for physicians and caregivers and lead to earlier institutionalization and increased social and economic costs. In this view, recent literature has considered the likely genetic component of BPSD in AD, defining different clusters. Several studies have investigated whether the main recognised genetic risk factor for late-onset AD, namely the apolipoprotein E (APOE) gene, is associated with BPSD, with conflicting results. The involvement of dopamine- or serotonin- related pathways and associated genetic variabilities has been demonstrated as being interesting candidates for the neuropsychiatry manifestations of dementia. Moreover, genetic variations of neurotrophins, such as brain-derived neurotrophic factor (BDNF), have been related to depression susceptibility in AD. In the present review, we summarise the current literature on genetic risk factors to BPSD susceptibility in AD and discuss future possible treatment strategies.

Amyloid β(1-40) peptide was immobilized on an Au-colloid modified gold electrode and an electrochemical impedance spectroscopy (EIS) system was elaborated for determining the association constants, Ka, between small molecular ligands and the peptide. The changes in the resistance of the modified electrode layer with deposited Aβ(1-40) peptide were measured with EIS in relation to a series of concentrations of the ligands studied. The association constants were calculated from Langmuir isotherms. The method is sensitive, reproducible and consumes only very little amounts of interacting species. The method was applied to determine the affinity of a series of pyridine and piperidine derivatives, mainly alkaloids of a known ability, to cross the blood-brain barrier. Along with nicotine and its main metabolite cotinine, the following agents were taken for the study: anabasine, arecoline, coniine, lobeline, pseudopelletierine, trigonelline, as well as pyridine and piperidine themselves. For the sake of comparison, two vitamins were also subjected to the study: ascorbic acid and pyridoxine. There was no association of these vitamins, which were tested as a negative control. For the compounds studied, a strong association with Aβ(1-40) was determined with Ka ranging from 1.7 x 107 M-1 for (±)- anabasine to 2.3 x 108 M-1 for arecoline hydrobromide. As a positive control, a well known amyloid specific binder, Congo Red, was tested, displaying Ka equal to 3.7 x 108 M-1.

This paper presents the results obtained with the innovative use of special types of artificial neural networks (ANNs) assembled in a novel methodology named IFAST (implicit function as squashing time) capable of compressing the temporal sequence of electroencephalographic (EEG) data into spatial invariants. The aim of this study is to test the potential of this parallel and nonlinear EEG analysis technique in providing an automatic classification of mild cognitive impairment (MCI) subjects who will convert to Alzheimer's disease (AD) with a high degree of accuracy. Eyes-closed resting EEG data (10-20 electrode montage) were recorded in 143 amnesic MCI subjects. Based on 1-year follow up, the subjects were retrospectively classified to MCI converted to AD and MCI stable. The EEG tracks were successively filtered according to four different frequency ranges, in order to evaluate the hypotheses that a specific range, corresponding to specific brain wave type, could provide a better classification (0.12 Hz, 12.2 - 29.8 Hz; 30.2 - 40 Hz, and finally Notch Filter 48 - 50 Hz). The spatial content of the EEG voltage was extracted by IFAST step-wise procedure using ANNs. The data input for the classification operated by ANNs were not the EEG data, but the connections weights of a nonlinear auto-associative ANN trained to reproduce the recorded EEG tracks. These weights represented a good model of the peculiar spatial features of the EEG patterns at scalp surface. The classification based on these parameters was binary and performed by a supervised ANN. The best results distinguishing between MCI stable and MCI/AD reached to 85.98%.(012 Hz band). And confirmed the working hypothesis that a correct automatic classification can be obtained extracting spatial information content of the resting EEG voltage by ANNs and represent the basis for research aimed at integrating spatial and temporal information content of the EEG. These results suggest that this low-cost procedure can reliably distinguish eyes-closed resting EEG data in individual MCI subjects who will have different prognosis at 1-year follow up, and is promising for a large-scale periodic screening of large populations at amnesic MCI subjects at risk of AD.