Current Alzheimer Research - Volume 3, Issue 2, 2006

Current Alzheimer Research presents the second issue of its third volume, which comprises nine articles from both primary research and review work. These articles report a combination of mechanism-based and clinicallyoriented translational studies that cover a wide range of Alzheimer's disease (AD) research from the cholinergic model; the role of amyloid, tau protein and metals; to oxidative stress. The present issue reports nine articles addressing the most exciting and relevant topics in the field of AD. Two papers discuss interactions of the amyloid beta peptide (Aβ)/Aβ precursor protein (APP) with other cellular systems, two papers highlight studies on anticholinesterase (AChE) inhibitors, one paper each presents studies on tau protein phosporylation, apolipoprotein E (APOE) genotype, mild cognitive impairment (MCI) and a promising treatment strategy. In addition, there is an interesting 'Commentary' on angiotensin converting Enzyme (ACE) inhibitor. Standridge presents (p 95-108) a comprehensive view of the neuropathophysiological mechanisms for AD, involving several vicious cycles. A number of interactive systems that each alone or together, once set in motion, amplify their own processes, thereby accelerating the development of AD. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition represent an example of vicious cycle. In addition, AD symptoms most likely result from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which follows and accelerates the initial pathology of AD. Heese and Akatsu summarize (p 109-121) both physiological and pathophysiological functions of APP and its cleavage product Aβ, based on recent data from genomics, proteomics and molecular genetics. This review provides an insight into interaction of APP and Aβ with other cellular systems present and their roles in the pathogenesis of AD. In addition to Aβ deposition, AD is characterized by the presence of paired helical filaments, mostly made up of hyperphosphorylated tau protein. However, the mechanism for tau phosphorylation and its interaction with metals are poorly understood and is an active field of current research. One of the important kinases that modifies tau protein is called GSK3. Herein, Gómez-Ramos and colleagues (p 123-127) discuss the effect of two metals, lithium and tungstate, on GSK3 (or tau I kinase) activity, and its important implications for AD. Mechanistic studies lead to the development of potential treatment strategies. This is important because currently available drugs transiently relieve some symptoms of AD but have no significant effects on the progression of the disease. Based on the prevailing "amyloid" hypothesis, preventing the formation of "bioactive" Aβ or inactivating previously formed bioactive Aβ is becoming a promising approach for treating AD. Liu and Schubert (p 129-135) describe a cell-based assay for detecting bioactive Aβ to screen for drugs that can inactivate bioactive Aβ. They discuss several promising compounds that can inactivate bioactive Aβ species, and this constitutes a promising approach for the potential treatment of AD. Research on currently available and FDA approved AChE inhibitor drugs reveal interesting results. Doganay and colleagues report (p 137-145) pharmacological manipulation of the vasoconstrictive effects of Aβ peptides by donepezil and rivastigmine. They postulate that such AChE inhibitor drugs mediate these vascular modulatory effects via an action on Aβ-mediated vasoconstrictor mechanisms rather than an independent action on endothelial or smooth muscle cell mediated responses. At the clinical level, Behl and colleagues determined if there are differential treatment effects of second-generation AChE inhibitors over one year. They report (p 147-156) that cholinesterase inhibitors slow decline in executive functions, rather than memory in AD based on this observational study. Notably, executive, language and visuospatial functions, rather than memory, seems to be more amenable to stabilization over one year by cholinesterase inhibitors in AD. In the area of genetic risk factors for AD, Sabbagh and colleagues report (p 157-160) studies on the effect of the APOE genotype on the lipid profile in AD. They report that APOE gene status has minimal influence on either the lipid panel or mean age of onset for AD. Interestingly, APOE gene dose influences the lipid panel with APOE ɛ2/2, and ɛ2/3 having significantly better lipid panels and later age of onset. In the area of predictors for AD, current research suggests that half of MCI patients convert to dementia within 3 years. Since not all patients convert to......

Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to its toxic forms (various forms of Abeta aggregation), and lastly the oxidative, inflammatory, and other effects of toxic Abeta. Fibrillar beta-amyloid peptide, a major component of senile plaques in AD brain, is known to induce microglial-mediated neurotoxicity under certain conditions, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. Abeta-42 oligomers that are soluble and highly neurotoxic, referred to as Abeta-derived diffusible ligands (ADDLs), assemble under conditions that block fibril formation. These oligomers bind to dendrite surfaces in small clusters with ligand-like specificity and are capable of destroying hippocampal neurons at nanomolar concentrations. Evidence is presented that AD is triggered by these soluble, neurotoxic assemblies of Abeta rather than the late stage pathology landmarks of amyloid plaques and tangles. The premise is that AD symptoms stem from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which nevertheless follows and exacerbates the initial pathologies of AD. The defective clearance of amyloid leads to amyloid angiopathy that in turn perpetuates hypoperfusion that affects formation as well as absorption of CSF thereby altering clearance of amyloid and promoting vascular and parenchymal deposition[ 1]. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition thus represent a vicious cycle. Chronic vascular hypoperfusion-induced mitochondrial failure results in oxidative damage, which drives caspase 3-mediated Abeta peptide secretion and enhances amyloidogenic APP processing. Intracellular Abeta accumulation in turn promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Abeta generation and oxidation, each accelerating the other. Abeta activates astrocytes that add to the oxidative imbalance, upregulate the expression of APP via TGF-beta, and are capable of expressing BACE1. Each of these 3 actions accelerates the larger cycle of cholinergic neuron destruction. As oxidative stress induces lesions of cholinergic nuclei producing a reduction in cholinergic neurotransmission, a subsequent increase in cortical APP involving PKCepsilon leads to accelerated amyloidogenic APP metabolism. The linkage of cholinergic activation and APP metabolism completes an additional feedback loop wherein the damage wrought by Abeta accelerates further Abeta production. A comprehensive vision of the neuropathophysiologic mechanisms that result in AD reveals several vicious cycles within a larger vicious cycle, that is to say, a number of interactive systems that each, once set in motion, amplify their own processes, thus accelerating the development of AD.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss in memory and deterioration of the higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques of aggregated amyloid-beta-peptide (Aβ), intracellular neurofibrillary tangles (NFTs) that consist of hyperphosphorylated tau protein (P-tau) and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Recent data obtained via genomics, proteomics and molecular genetics, have gleaned new information with regard to the physiological and pathophysiological functions of the amyloid precursor protein (APP) and its cleavage product Aβ. This review glances over several aspects that may play a major role in the pathogenesis of AD providing an insight into APP's and Aβ's interplay with other cellular systems.

One of the main pathological characteristics of Alzheimer's disease is the presence in the brain of the patients of an aberrant structure, the paired helical filaments, composed of hyperphosphorylated tau. The level of tau phosphorylation has been correlated with the capacity for tau aggregation. Thus, the mechanism for tau phosphorylation could be important to clarify those pathological features in Alzheimer's disease. Tau protein could be modified by different kinases, being GSK3 the one that could modify more sites of that protein. GSK3 activity could be modulate by the presence of metals like magnesium that can be required for the proper function of the kinase, whereas, metals like manganesum or lithium inhibit the activity of the kinase. Many works have been done to study the inhibition of GSK3 by lithium, a specific inhibitor of that kinase. More recently, it has been indicated that sodium tungstate could also inhibit GSK3 through a different mechanism. In this review, we discuss the effect of these two metals, lithium and tungstate, on GSK3 (or tau I kinase) activity.

Treating Alzheimer's disease (AD) is one of today's biggest unmet medical needs. The drugs currently available transiently relieve some symptoms but have no significant effects on the progression of the disease. Progress in the past decade suggests that the amyloidogenesis of the inactive monomeric amyloid β peptide (Aβ) into a subset of toxic Aβ polymers is responsible for neurodegeneration in AD. Not all forms of Aβ aggregates are damaging, for there are patients whose brains accumulated large amounts of Aβ in the form of plaques, but they had no obvious neurodegeneration and symptoms of dementia. Since Aβ can polymerize into many types of polymers or aggregates, the form of Aβ that induces neurodegeneration in AD, defined here as bioactive Aβ, is not clear. Preventing the formation of bioactive Aβ or inactivating previously formed bioactive Aβ is a promising approach for treating AD. This review describes our efforts to develop a cell-based assay for detecting bioactive Aβ, to verify the concept of bioactive Aβ in an animal model of AD and in post mortem brain tissue from AD patients, and to use this assay to screen for drugs that can inactivate bioactive Aβ. These studies show the proof in principle that inactivating bioactive Aβ is a promising approach to treat AD. Several promising compounds that can inactivate bioactive Aβ species are also described.

The amyloid-b (Aβ) peptide has been linked to the pathology of Alzheimer's disease (AD). There is now evidence to support a vasoconstrictive effect of Aβ protein that could be detected in peripheral skin microvasculature. In this study we investigated the ability of acetylcholinesterase (AChE) inhibitors, Donepezil and Rivastigmine, to modulate the vasoconstrictor activity of Aβ25-35 and Aβ1-40. The ability of these drugs to improve endothelial mediated vascular responses to acetylcholine and bradykinin subsequent to perfusion of Aβ peptides was also investigated. The vascular responses to Aβ peptides, acetylcholine, bradykinin and sodium nitroprusside and their modulation by acetylcholinesterase inhibitors were examined in the base of a vacuum induced blister raised on the rat hind footpad using laser Doppler flowmetry. Aβ25-35 (1μM) and Aβ1-40 (0.1μM) induced a vasoconstrictor effect and significantly reduced the vasodilator response to acetylcholine (100μM) and bradykinin (1μM). Donepezil (100μM) and Rivastigmine (100μM) both reduced the vasoconstrictor effect of Aβ peptides, and significantly restored the endothelial vascular response to acetylcholine. Similarly, Donepezil significantly restored the endothelial vascular response to bradykinin. The results also showed that the actions of acetylcholinesterase inhibitors are independent of a direct action on smooth muscle cell reactivity or on endothelial cell function in the absence of Aβ. The current study provides the first evidence in vivo to suggest that acetylcholinesterase inhibitors modulate the vasoconstrictive effects of Aβ peptides at the level of skin microvasculature. We raise the notion that Donepezil and Rivastigmine mediate these vascular modulatory effects via an action on Aβ-mediated vasoconstrictor mechanisms rather than an independent action on endothelial or smooth muscle cell mediated responses.

To determine if there are differential treatment effects of second-generation cholinesterase inhibitors over one year, 130 patients (untreated=65, treated=65) meeting NINCDS-ADRDA criteria for mild or moderate probable AD underwent standardized cognitive testing at baseline and 12 months later at a university memory clinic. Patients were followed either prior to or after the availability of treatment and were matched on education and baseline Mini Mental State Examination (MMSE). A detailed medical history evaluation was conducted. In this well matched longitudinal observational cohort study, there were no differences in the prevalence of comorbid illnesses, concomitant medication use or vascular risk factors except for a greater number of treated patients with a previous history of smoking. Separate repeated measures MANCOVAs on the MMSE, Mattis Dementia Rating Scale (DRS), and its 5 subscores (attention, initiation/ perseveration, conceptualization, construction and memory) (Bonferroni corrected), after covarying for the effects of smoking, and SSRI use, showed less decline over one year in the treated group in overall cognition and in all subscores of the DRS except for memory (effect sizes 0.5-0.7). Less decline was also seen in the treated group in function and in instrumental and basic activities of daily living as measured with the Disability Assessment for Dementia Scale (DAD) (effect sizes 0.4-0.8). Executive, language and visuospatial functions, rather than memory, appeared to be more amenable to stabilization over one year by cholinesterase inhibitors in AD.

Objective: To determine whether Apolipoprotein E4 (Apo E4) gene status or ApoE gene dose affect the lipid profile in AD. Background: Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the influence of the Apo E genotype on the lipid profile characteristics in AD. Methods: We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 142 subjects with probable or possible AD (mean age 76.5 ± 8.9 years), not on lipid lowering therapy by Apo E genotype. Assessment was done by gene status and gene dose. Results: ApoE4 gene status did not reveal any significant differences in the lipid profile except for LDL. However, significant differences were observed by ApoE gene dose. Conclusion: ApoE gene status has minimal influence on the lipid panel or mean age in AD. Apo E gene dose does influence the lipid panel with Apo E 2/2, and 2/3 having significantly better lipid panels and older age of onset.

BACKGROUND. Mild Cognitive Impairment is a common condition defined as transitional state between normality and dementia of Alzheimer type. Clinically is characterized by subjective and objective memory loss beyond the expected for age and educational level, although a broad range of cognitive inefficiencies may appear, with preservation of daily living activities. Approximately half the patients convert to dementia within 3 years. Since no all patients convert to dementia it is essential to find reliable predictors so as to start the appropriate treatment as soon as possible. METHOD. Extensive Medline-based search for articles dealing with predictors of conversion to dementia in Mild Cognitive Impairment (MCI). RESULTS. There is a substantial body of literature dealing with predictors of dementia in patients with MCI. These predictors range from a simple delayed recall task on Mini-Mental to sophisticated radiological techniques and CSF biomarkers. Comprehensive neuropsychological tests rarely surpass 70% sensitivity and specificity. The presence of the APOE epsilon 4 allele has been associated with increased risk of conversion but the sensitivity is quite low. CSF biochemical markers are being developed with encouraging results. β-amyloid 42 protein is usually lower in converters than in people with stable cognitive status and tau protein is higher. The sensitivity is substantial but specificity is so far low. An epitope of tau protein (P231) looks more specific of Alzheimer's disease and therefore a promising biomarker. In the blood, high β-amyloid protein levels indicate risk of conversion but only a few studies have been published. Hippocampal or entorhinal atrophy on MRI is one of the most used radiological markers of conversion but quantification of atrophy is not simple as it is subject to artifacts and anatomic variations. Proton Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) are emerging as the most promising predictive tools. The highest degree of accuracy (>90%) has been achieved by means of PET plus either memory performance or APOE4 genotype. However, the samples of the published studies are mostly small, and these instruments are not widely available. CONCLUSIONS. There is no enough evidence to recommend specific techniques for predictions. Until an accurate marker is developed, a combined use of cognitive tests, APOE genotype, and a neuroradiological technique is probably the best option for prediction purposes depending on availability and experience.