Current Alzheimer Research - Volume 5, Issue 1, 2008

Current Alzheimer Research has successfully completed four years of publication-reporting novel findings and reviewing major accomplishments in the field of Alzheimer's disease (AD). With this confidence, Current Alzheimer Research is presenting its fifth volume to pursue, without interruption, the journal's core mission of disseminating new knowledge about AD. During the last year, the journal has published five issues in its fourth volume in a timely manner, as promised [1]. The fourth volume alone (including five issues) has featured a total of 78 articles and 4 editorials. These articles, comprising ‘research’ and ‘review’ studies have succeeded in capturing the most recent advances in AD research. Briefly, various leading experts from different sub disciplines of AD have articulated on a wide range of topics such as potential disease-specific molecular markers, cholinesterase inhibitors, vaccination, oxidative stress, tauopathy and obesity and dementia as related to AD. Several unique and controversial topics have been presented in order to encourage ground breaking research in novel directions. These articles discuss basic science questions reported from neuronal cell culture and animal studies as well as human-based clinical studies. Moreover, the fourth volume published three ‘hot topics’ issues, which have comprehensively updated some interesting themes related to AD. The fourth volume of Current Alzheimer Research is enriched by international contributors hailing from at least 16 countries: Australia, Austria, Brazil, Canada, France, Germany, India, Iran, Ireland, Israel, Italy, Spain, Sweden, UAE, UK and the USA. The articles, beginning from the first volume (and the first issue) of the journal, have been listed in Pub- Med/MEDLINE. In addition, the journal is indexed in the ‘Alzheimer Research Forum’, ‘Current Contents’ and PsycINFO databases. Current Alzheimer Research has also been selected for coverage in the Thomson Scientific products and services, such as ‘Science Citation Index Expanded’ (also known as SciSearch®),‘Neuroscience Citation Index®’, ‘Journal Citation Reports/Science Edition®’, ‘BIOSIS Previews’ and ‘BIOSIS Reviews Reports and Meetings’. The Bentham Science publisher is providing free online Abstracts of each article and the complete Editorial on the journal's website (http://www.bentham.org/car/). The main thrust in this year's, the fifth, volume of Current Alzheimer Research remains reporting both mechanismoriented and translational-based research in the field of AD and other dementias. Drug target developments, brain imaging, morphometeric studies and pharmacological research will be other areas of discussion in the journal. Furthermore, Current Alzheimer Research will continue to report results from clinical drug trials that will also consist of properlyjustified, evidence-based negative data. AD is an active and fast emerging field of research, as exemplified by the fact that an ‘Alzheimer's disease’ search captures over 4,100 citations on PubMED/MEDLINE during the last year, alone. Therefore, in addition to timely dissemination of this knowledge, it is a great necessity to collate the vast literature and extract its essence in thorough review articles. By discussing research studies from both primary research and presenting review articles, Current Alzheimer Research will continue to make an important contribution and provide a valuable resource to the AD field. In the fifth volume, Current Alzheimer Research plans to present six different issues describing different areas of AD research as critical review and original research articles. This work should address the mechanism of neurodegeneration and neurobiological aspects of AD, investigate potential new drug targets and analyze novel therapeutic approaches. Current Alzheimer Research will cover research topics that employ behavioral, cellular, genetic and in vivo models. The fifth volume will continue to publish the widely popular ‘Hot Topic’ issues, which are based on a particular theme of AD research and are written by a group of renowned experts in the field. Indeed, the next issue of the journal will be a special ‘Hot Topic’ issue entitled “Production and fate of amyloid peptides: Recent advances and perspectives” (Guest Editor: Dr. Frederic Checler). Another ‘Hot Topic’ issue lined up for future publication is related to “Structurefunction implications in Alzheimer's disease pathology” (Guest Editors: Drs. Hermona Soreq and Ehud Gazit). Such important contributions are the key to success and progress for Current Alzheimer Research. The first issue of the 5th volume of Current Alzheimer Research presents eleven selected articles that describe some of the most exciting and emerging topics in the field of neurodegeneration and their potential utility to develop drug targets for the treatment of AD..........

Advances in Alzheimer Disease (AD) research suggest that central nervous system (CNS) lipids play a key role in the pathogenesis. This role is attributed to the rich lipid content of CNS structures and the presence of blood brain barrier which disables the exchange of lipids between CNS and plasma. Among these lipids, cholesterol is a unique molecule provided mainly by its de novo synthesis in the CNS. Special apolipoproteins used for its efficient recycling within the CNS and special oxysterols formed that are specific to brain all contribute to the unique properties of the molecule. Above all, the presence of cholesterol in the membrane enables it to function as a regulator of a number of protein related processes such as the β-amyloid precursor protein cleavage. Cholesterol reducing agents such as statins are recently proposed to have a protective role in AD. This review will focus on the role of cholesterol metabolism and genetics in AD. Current literature investigating the relationship between cholesterol and AD will be evaluated from the pathophysiological perspective. Genetic studies concerning proteins which are involved in the CNS cholesterol metabolism will also be summarized in the hope that genomics may stimulate further studies and thus contribute to a more clear understanding of the molecular mechanisms in the pathophysiology of AD.

The LDL receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer's disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/ apolipoprotein E (ApoE) uptake, with the η4 allele of ApoE as the strongest genetic risk factor for late-onset AD. It has been established that the cholesterol metabolism of the cell has a strong impact on the production of Aβ, the major component of the plaques found in the brain of AD-patients. The original report that soluble amyloid precursor protein (APP) containing the kunitz proteinase inhibitor (KPI) domain might act as a ligand for LRP1 led to a complex investigation of the interaction of both proteins and their potential function in AD development. Meanwhile, it has been demonstrated that LRP1 might bind to APP independent of the KPI domain in APP. This APP - LRP1 interaction is facilitated through a trimeric complex of APP-FE65-LRP1, which has a functional role in APP processing. Along with LRP1, APP is transported from the early secretory compartments to the cell surface and subsequently internalised into the endosomal / lysosomal compartments. Recent investigations indicate that ApoER2 and SorLA fulfil a similar role in shifting APP localisation in the cell, which affects APP processing and the production of the APP derived amyloid β-peptide (Aβ). In addition to the effect of lipoprotein receptors on APP processing and Aβ production, LRP1 has been shown to bind Aβ directly or indirectly through Aβ-lactoferrin, Aβ-α2M and Aβ-ApoE complexes in vitro and in vivo. Based on these observations two LRP1 mediated clearance mechanisms of Aβ are proposed to play a crucial role in the prevention of AD: either Aβ-uptake into a cell with its subsequent degradation or its transport out of the brain over the blood brain barrier into the periphery. Following this export Aβ is degraded in the liver, where LRP1 potentially conducts the removal of Aβ from the blood stream. Although the involvement of LDLR family members in AD is not yet fully understood it becomes clear that they can directly affect APP production, Aβ-clearance and Aβ-transport over the blood brain barrier.

Alzheimer's Disease (AD) is caused by the deposition of insoluble and toxic amyloid peptides (Aβ) in the brain leading to memory loss and other associated neurodegenerative symptoms. To date there is limited treatment options and strategies for treating AD. Studies have shown that clearance of the amyloid plaques from the brain and thus from the blood could be effective in stopping and or delaying the progression of the disease. Small peptides derived from the Aβ- 42 sequence, in particular KLVFF, have shown to be effective binders of Aβ peptides and thus could be useful in delaying progression of the disease. We have taken advantage of this property by generating the retro-inverso (RI) version of this peptide, ffvlk, in different formats. We are presenting a new detox gel system using poly ethylene glycol (PEG), polymerized and cross linked with the RI peptides. We hypothesize that detox gel incorporating RI peptides will act like a ‘sink’ to capture the Aβ peptides from the surrounding environment. We tested these detox gels for their ability to capture biotinylated Aβ-42 peptides in vitro. The results showed that the detox gels bound Aβ-42 peptides effectively and irreversibly. Gels incorporating the tetramer RI peptide exhibited maximum binding capacity. The detox gel could be a potential candidate for treatment strategies to deplete the brain of toxic amyloid peptides.

Alzheimer's disease (AD) is a neurological disorder characterized by plaques and an elevated immune response. Specifically, increased expression of interleukin (IL)-1 and tumour necrosis factor (TNF)-α, has been observed in AD cerebrospinal fluid and temporal brain tissue. Both of these immunomodulators were shown to carry genetic variants that increase the risk of developing AD. Studies have also established the apolipoprotein E (apoE) gene to be a risk factor for AD with η4 carriers having been found to show lower levels of brain apoE. In the present study, treatment of primary rat mixed glial cell cultures with IL-1β induced a significant increase in extracellular apoE protein. In contrast, treatment primary rat astrocyte and mixed glial cell cultures with TNF-α significantly reduced extracellular apoE protein levels. These results are consistent with the notion that elevated cytokine expression directly modulates immunosuppression and indirectly apoE-mediated neuronal remodeling.

Alzheimer's disease (AD) is the most common diagnosis among dementia. As increasing longevity results in larger numbers of AD patients and thus rising economic costs, there has been intense research about the pathophysiology and treatment strategies during the last years. Since neurotrophic factors are not only responsible for neuronal development but also critical for the maintenance of neurons, they represent mediators of high interest within the research of neurodegeneration. Thereby, NGF has been identified as a dynamic pattern during the time course of neurodegeneration in AD. Post mortem studies point to a lack of NGF action in early stages of AD. In contrast NGF is found in enhanced concentrations in brains with severe AD partly due to a pathologically altered axonal transport of NGF in the neurons. Therefore, pharmacological interventions starategies focus on an neurotrophin substitution in mild to moderate cases of AD. Intensive research mostly in rodents has recently led to first promising clinical trials of intracerebral neurotrophin application pointing to a growing role of neurotrophins in the establishment of new pharmacological strategies concerning AD.

Estrogen exerts beneficial effects on the brain throughout life. Studies demonstrate that estrogen is neuroprotective and that reduced brain estrogen activity may influence the clinical course of Alzheimer's disease (AD). Changes in levels of estrogen receptors have been detected in postmortem brain tissue of AD patients. Very little is known about the relationship between clinical stage and levels of estrogen receptors in postmortem brain. We hypothesized that estrogen receptor levels would be related to severity of cognitive impairment assessed proximate to death. Western blotting was used to quantify ER-α and ER-β in nuclear, cytosolic, and crude membrane fractions of superior frontal cortex from 25 AD patients. Multiple linear regression analyses adjusted for age, sex, and education showed a significant linear relationship between Mini-Mental State Examination score (MMSE) and wild-type nuclear ER-α (â = 5.463, p = 0.03), but none between MMSE and wild-type nuclear ER-β (â = 2.29, p = 0.36). We incidentally observed additional higher and lower molecular mass bands for ER-α in study subjects. Additional experiments performed on frontal cortex nuclear fractions prepared from subjects enrolled in a different study confirmed that these same bands are present in female and males with and without AD. Together our data show a relationship between wild-type ER-α and level of cognitive impairment in AD, and also suggest the possibility that variant isoforms of ER-α may be present in frontal cortex of patients with and without AD.

Dementia is a common, chronic and progressive illness. Many different types of dementia exist. It is important to have knowledge of the various dementia presentations so that the clinician can differentiate one type from another. Past and current approaches of classifying dementias are reviewed in this paper. The past cortical/subcortical scheme is reviewed as well as the current synucleinopathy/tauopathy scheme. This paper focuses on the most common synucleinopathies and tauopathies including Alzheimer's Dementia, Dementia with Lewy Bodies, Parkinson's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy, Multiple System Atrophy and Corticobasal Ganglionic Degeneration. We systematically approach each dementia and review cognitive, psychiatry and neurological features of each. We also compare and contrast each dementia and the synucleinopathies and taupoathies alike. Our goal is to provide the clinician with sufficient knowledge to competently and confidently diagnose a patient who presents with progressive cognitive decline and deterioration in functioning.

Objetive: The study aimed to describe the prevalence and severity of neuropsychiatric symptoms in patients with Alzheimer's disease (AD) and vascular dementia (VaD). Patients and methods: We prospectively studied 65 patients with dementia, 37 met the criteria of NINCDS-ADRDA for probable AD and 28 the clinical and radiological criteria of NINDS-AIREN for VaD. Among VaD patients, 22 met the radiological criteria for subcortical VaD. The Minimental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were used to evaluate cognitive and neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs. Results: Age, gender, educational level and MMSE scores did not differ between patients (p >0.05). The total prevalence of neuropsychiatric symptoms was similar in both groups (AD 94.6% vs. VaD 96.4%, p= 0.727). Sleep disturbances (35.1% v 3.6%, p =0.002) and appetite changes (37.8% v 14.3%, p = 0.032) were more prevalent in AD patients than in VaD patients who met the NINDS-AIREN criteria. Sleep disturbances (35.1% v 4.5%, p=0.008), appetite changes (37.8% v 13.6%, p = 0.047) and aberrant motor behaviour (24.3% v 0%, p =0.012) were more prevalent in AD patients than in subcortical VaD. The total scores for sleep disturbance, appetite changes and aberrant motor behavioural were higher in AD patients (p < 0.05). Conclusions: There were no significant differences between AD and VaD patients, except that sleep disturbances, appetite changes and aberrant motor behaviour that were more prevalent and severe in AD.

Background: Several demographic, environmental and clinical risk factors have been determined as possible risk/protective factors of Alzheimer's disease (AD). The purpose of this study was to find out which one of these known factors is related to developing of AD in Iranian population. Materials and Methods: In a case-control study, 115 elderly patients (mean age of 70±8.18 years) with DSM-IV based final diagnosis compared with 115 non-demented counterparts matched for age ,sex, and socioeconomic status regarding lifestyle, family history, and history of bio-psychosocial health. Results: All differences between the two groups were non-significant except for history of hypertension (P=0.018) which was most prevalent in AD group. Risk of the incident AD for the hypertensive group was 1.71 (1.08-2.70) compared to the non-hypertensive group. Conclusion: These results confirm the previously reported relationship between AD and vascular factors. Prevention, early detection, and treatment of hypertension may have some implications in the primary and secondary prevention of AD.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis - a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive sideeffects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Objective: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimer's disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. Methods: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL23), Neuropsychiatric Inventory (NPI), and MMSE. Results: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. Conclusions: In this trial, memantine did not show an advantage over placebo based on protocol- specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.