Dementia In Elderly Population Research Articles

Alterations in the Expression of Amyloid Precursor Protein Cleaving Enzymes mRNA in Alzheimer Peripheral Blood.

Alzheimer's disease (AD) is the most common cause of dementia in elderly populations. Changes in the expression of the Amyloid Precursor Protein (APP)-cleaving enzymes directly affect the formation of Amyloid Beta (Aβ) plaques, a neuropathological hallmark of AD. We used peripheral blood from AD patients to investigate the expression of genes related to APP-processing [(β-site APP-cleaving enzyme 1 (BACE1), presenilin1 (PSEN1), and a disintegrin and metalloproteinase family 10 (ADAM10) and 17 (ADAM17)] and the epigenetic genes sirtuin (SIRT)1-3, which regulate Aβ production. Real-time polymerase chain reactions were performed to determine the specific mRNA levels in plasma. The mRNA levels in AD patients were compared to those in healthy persons and assessed in relation to the subjects' cognitive performance. BACE1 mRNA level in AD subjects was significantly higher than those of healthy controls, whereas ADAM10 level was significantly lower in the AD subjects. The SIRT1 level was significantly decreased, while that of SIRT2 was increased in AD subjects and elderly controls compared to levels in healthy young control. In addition, correlations were found between the expression levels of BACE1, ADAM10 and SIRT1 and cognitive performance scores. Total Aβ (Aβ40+Aβ42) levels and the Aβ40/Aβ42 ratio were significantly increased in the AD subjects, whereas decrease in plasma Aβ42 was found in AD subjects. There was a negative correlation between Aβ40 or total Aβ and Thai Mental State Examination (TMSE) while there was no correlation between Aβ40/Aβ42 ratio or Aβ42 and TMSE. The present findings provide evidence and support for the potential roles of these enzymes that drive Aβ synthesis and for epigenetic regulation in AD progression and development, which can possibly be considered peripheral markers of AD.

Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (Aβ) protein. Aβ is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme ‘transmembrane aspartyl protease, β-secretase’. Inhibition of β-secretase is a viable strategy to prevent neurotoxicity in AD. Another strategy in the treatment of AD is inhibition of acetylcholinesterase. This inhibition reduces the degradation of acetylcholine and temporarily restores the cholinergic function of neurons and improves cognitive function. Monoamine oxidase and higher glutamate levels are also found to be linked with Aβ peptide related oxidative stress. Oxidative stress leads to reduced activity of glutamate synthase resulting in significantly higher level of glutamate in brain. The aim of this study is to perform in silico screening of a virtual library of biaryl scaffold containing compounds potentially used for the treatment of AD. Screening was done against the primary targets of AD therapeutics, acetylcholinesterase, β-secretase (BACE1), Monoamine oxidases (MAO) and N-Methyl-D-aspartate (NMDA) receptor. Compounds were screened for their inhibitory potential by employing molecular docking approach using AutoDock vina. Binding energy scores were embodied in the heatmap to display varies strengths of interactions of the ligands targeting AD.ResultsSeveral ligands showed notable interaction with at least two targets, but the strong interaction with all the targets is shown by very few ligands. The pharmacokinetics of the interacting ligands was also predicted. The interacting ligands have good drug-likeness and brain availability essential for drugs with intracranial targets.ConclusionThese results suggest that biaryl scaffold may be pliable to drug development for neuroprotection in AD and that the synthesis of further analogues to optimize these properties should be considered.

Serum Vitamin D Concentrations and Cognitive Change Over 20 Years: The Atherosclerosis Risk in Communities Neurocognitive Study

Background/Aims: 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with cognitive decline and incident dementia in elderly populations; however, these relationships are susceptible to reverse causation. Less is known about the association of midlife 25(OH)D with long-term cognitive decline. Methods: This was a prospective cohort study of 13,044 participants (mean age 57 years at baseline) in the Atherosclerosis Risk in Communities Study. 25(OH)D was measured from serum collected at baseline (1990–1992) using liquid chromatography tandem high-sensitivity mass spectrometry. Cognition was assessed using 3 neuropsychological tests at 3 time points, which were combined into a composite cognitive Z-score. Multivariable-adjusted linear mixed-effects models with random intercepts and slopes were used to estimate associations between 25(OH)D and cognitive change over 20 years. Results: Compared to persons with sufficient 25(OH)D (≥30 ng/mL), those with deficient (< 20 ng/mL) and intermediate (20–< 30 ng/mL) 25(OH)D concentrations had similar cognitive decline in composite cognitive Z-scores (deficient versus sufficient: –0.035 [95% CI –0.104 to 0.033] and intermediate versus sufficient: –0.029 [95% CI –0.080 to 0.023]). Conclusions: Lower concentrations of 25(OH)D measured in midlife were not significantly associated with more rapid cognitive decline over a 20-year follow-up period. The results of this prospective study are less susceptible to reverse causation than prior studies.

Biospectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Aging Mouse Model.

Western society is facing a health epidemic due to the increasing incidence of dementia in aging populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Aging is the greatest risk factor for memory loss that occurs during the natural aging process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Greater understanding of the biochemical pathways that drive a healthy aging brain toward dementia (pathological aging or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein overexpression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural aging process. A promising animal model reported to model mechanisms of accelerated natural aging and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain aging. A limitation to traditional methods of biochemical characterization is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or microspatial resolution. Therefore, in this investigation, we report the first multimodal biospectroscopic characterization of the SAMP8 model, and have identified important biochemical and elemental alterations, and colocalizations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of Zn deficiency within specific subregions of the hippocampal CA3 sector, which colocalize with decreased lipid unsaturation. Our findings also revealed colocalization of decreased lipid unsaturation and increased lactate in the corpus callosum white matter, adjacent to the hippocampus. Such findings may have important implication for future research aimed at elucidating specific biochemical pathways for therapeutic intervention.

Genetic and Environmental Risk Factors of Alzheimer's Disease

Alzheimer’s is one of the most common neurodegenerative disease generally found in the form of dementia in elderly population. Advanced age is still considered as most important risk factor for this disease. A complicated array of molecular events has been implicated behind this disease. As AD is chronic neurodegenerative disease and etiology is still unclear, familial AD accounts only 5% of the disease. Then it is more important to look for other factors that play great role in the onset of the disease. Thus, this paper reviews the role of genetics, different environmental, oxidative stress factors and its mechanistic insights underlying the pathogenesis of Alzheimer’s disease.

The Importance of Identifying Early Changes in Cardiac Structure and Function for the Prevention of Cognitive Impairment and Dementia.

Multiple cardiac pathologies have been shown to contribute to progressive cognitive decline and dementia in elderly populations, including left ventricular hypertrophy (LVH), a marker of prolonged exposure to hypertension. Although associations between chronic hypertension and cognitive function are thought to be mediated primarily by these end organ effects, there is increasing evidence that early changes in cardiac structure and function, such as LVH, may independently contribute to cognitive decline and impairment. In the current issue of the Journal of Alzheimer's Disease, Mahinrad and colleagues report important new findings on the association between LVH and cognitive function that are incremental to cardiovascular risk and co-morbidity, including hypertension. Emerging evidence that early changes in cardiac structure and function may independently contribute to cognitive decline in elderly populations has resulted in an increased interest in these preclinical substrates as potential treatment targets for the prevention of cognitive decline and in their putative contributions to the pathogenesis of dementia.

Walking Pace and the Risk of Cognitive Decline and Dementia in Elderly Populations: A Meta-analysis of Prospective Cohort Studies.

Data on the longitudinal association of walking pace with the risk of cognitive decline and dementia are inconsistent and inconclusive. Therefore, researchers conducted a meta-analysis of prospective cohort studies to quantitatively assess the association of walking pace with the risk of cognitive decline and dementia among elderly populations. Eligible studies were searched in PubMed and EMBASE through April 22, 2016. Additional information was retrieved through Google Scholar or hand review of the reference lists from the relevant studies. Prospective cohort studies were included if they reported relative risk (RR) and the corresponding 95% confidence interval (CI) of cognitive decline or dementia in relation to walking pace. Seventeen studies were identified, including 10 studies reporting the RR of cognitive decline (9,949 participants and 2,547 events) and 10 presenting the RR of dementia (14,140 participants and 1,903 events). Comparing the lowest to the highest category of walking pace, the pooled RR was 1.89 (95% CI = 1.54-2.31) for cognitive decline and 1.66 (95% CI = 1.43-1.92) for dementia. With every 1 dm/s (360 m/h) decrement in walking pace, the risk of dementia was increased by 13% (RR = 1.13; 95% CI = 1.08-1.18). This meta-analysis provides accumulated evidence supporting that slow or decreased walking pace is significantly associated with elevated risk of cognitive decline and dementia in elderly populations.

Multiple Targets for the Management of Alzheimer's Disease.

AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails.

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer’s disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

Dementia in a tribal landlocked elderly population at high altitude: What explains the lower prevalence?

Introduction:Studies across the populations have suggested that dementia is differentially distributed with a lower prevalence in developing regions than the developed ones. A comparison in the prevalence of dementia across populations may provide an insight into its risk factors. Earlier, we reported on the prevalence of dementia in elderly population in migrant, urban, rural, and tribal populations. The present study was conducted with a view to estimating the prevalence of dementia in Tribal Landlocked Elderly Population at high altitude and therefore to draw some conclusions on the differential distribution of dementia across populations.Methods:A cross-sectional comprehensive two-phase survey of all residents aged 60 years and older was conducted. Phase 1 involved screening of all individuals aged 60 and above with the help of a cognitive screen specifically developed for the tribal population. Phase 2 involved clinical examination of individuals who were suspected of dementia as per the developed cognitive screening test.Results:The results revealed that six individuals out of a total of 481 studied above 60 years of age in the studied population scored between 17 and 23, thus qualifying as suffering from mild cognitive impairment. Importantly, none of the individuals above 60 years of age scored <17.Discussion:The current study is in conformity with our previous study conducted on urban, rural, and migrant areas of the state of Himachal Pradesh again emphasizing on dementia being rare in tribal populations and thereby pointing to the presence of some protective factors among tribal people.

Can Walking Pace Predict The Risks Of Cognitive Decline And Dementia In Elderly Population?

The estimated numbers of dementia patients may increase to 115 million by 2050 in worldwide, thus early detection of the development of cognitive decline and dementia would potentially be of substantial benefits to the patients, families and society. Although some evidence from qualitative systematic review has indicated an inverse association between walking pace and cognitive dysfunction, the magnitude of the association has not been systematically investigated and remains unclear. PURPOSE: To quantitatively assess the association of walking pace with the risk of cognitive decline and dementia among elderly population through a meta-analysis of prospective cohort studies. METHODS: The relevant prospective cohort studies were identified by searching the PubMed and Embase database through October 2015. The association between walking pace and the risks of cognitive decline and dementia was expressed as weighted RR as comparing the lowest to the highest level of walking pace, and dose-response relation. Random-effects model was used in all analyses. RESULTS: A total of 16 articles were included. Seven/six articles investigated only cognitive decline/dementia as primary outcome, while other 3 articles examined both. 1) Comparing the lowest to the highest level of walking pace, a significant increased risk of cognitive decline was observed among 7 articles (RR=1.89; 95% CI=1.54-2.31), but no linear relation was observed among 3 studies (RR=1.09; 95% CI=0.96-1.23). 2) The pooled RR indicated slow walking pace significantly increased the risk of dementia (RR=1.67; 95% CI=1.41-1.97), comparing to the highest level of walking pace. The linear trend analysis included 3 articles, a significant dose-response relation was observed (RR=1.13; 95% CI=1.08-1.18). CONCLUSION: Our meta-analysis of prospective cohort studies indicates slow walking pace significantly increases the risks of cognitive decline and dementia among elderly people. In light of its characteristics of safety, cost-effectiveness, easy to test and interpret, we suggest walking pace as an effective indicator of the development of cognitive decline and dementia in elderly population.Supported by SSTC Grant (12XD1404500), SUS Grant (stfx20150101) and HSSYFME Grant (15YJC890029).

An increased risk of reversible dementia may occur after zolpidem derivative use in the elderly population: a population-based case-control study.

We evaluate the effects of zolpidem use to develop dementia or Alzheimer disease from the Taiwan National Health Insurance Research Database (NHIRD).A retrospective population-based nested case–control study. Newly diagnosed dementia patients 65 years and older and controls were sampled. A total of 8406 dementia and 16,812 control subjects were enrolled from Taiwan NHIRD during 2006 to 2010. The relationships between zolpidem use and dementia were measured using odds and adjusted odds ratios. The relationship between the average cumulative doses for zolpidem and dementia was also analyzed.Zolpidem alone or with other underlying diseases, such as hypertension, diabetes, and stroke, was significantly associated with dementia after controlling for potential confounders, such as age, sex, coronary artery disease, diabetes, anti-hypertension drugs, stroke, anticholesterol statin drugs, depression, anxiety, benzodiazepine, anti-psychotic, and anti-depressant agents’ use (Adjusted OR = 1.33, 95% CI 1.24–1.41). Zolpidem use also has significant dose–response effects for most of the types of dementia. In patient with Alzheimer diseases, the effects of zolpidem among patients with Alzheimer's disease remained obscure. The adjusted OR for patients whose cumulative exposure doses were between 170 and 819 mg/year (adjusted OR: 1.65, 95% CI 1.08–2.51, P = 0.0199) was significant; however, the effects for lower and higher cumulative dose were not significant.Zolpidem used might be associated with increased risk for dementia in elderly population. Increased accumulative dose might have higher risk to develop dementia, especially in patients with underlying diseases such as hypertension, diabetes, and stroke.

MicroRNA Expression Analysis of Adult-onset Drosophila Alzheimer’s Disease Model

Alzheimer's disease (AD) is the most common reason for dementia in elderly population. Its neuropathological features include senile plaques, neurofibril tangles and neuronal death. Scientists have established many AD animal models, including yeast, Caenorhabditis elegans, Drosophila melanogaster, mice, rats and non-human primates. Drosophila AD models are much more efficient for genetic manipulation and screening assay than mammals. microRNAs (miRNAs) are ~22nt small RNA molecules that fine-tune gene expression at posttranscriptional level. The dysregulation of miRNAs could participate in AD progression by influencing targets' expression and functions. However, miRNA expression profile of AD flies has not yet been investigated. Using the latest µParaflo™ miRNA microarray assay, we found that 17 miRNAs that were consistently dysregulated in adult-onset AD Drosophila brains: eight of which were upregulated (miR- 8, miR-13b, miR-277, miR-279, miR-981, miR-995, miR-998, miR-1017) and nine were downregulated (let-7, miR-1, miR-9a, miR-184, miR-193, miR-263b, miR-276a, miR-285, miR-289). KEGG pathway annotations using DIANA miRPath or targets predicted by Targetscan identified 7 pathways (Valine, leucine and isoleucine degradation; MAPK signaling pathway; Dorso-ventral axis formation; Propanoate metabolism; Sphingolipid metabolism; Lysine degradation; Jak- STAT signaling pathway) which might be influenced by these miRNAs. Integrative miRNA/mRNA regulatory network analysis revealed functional cluster with transaminase activity to be potentially regulated by miRNAs in AD. Taken together, our profiling assay identified miRNAs as markers for adult onset AD Drosophila. Dysregulation of miRNA profile may participate in AD pathogenesis by interrupting the metabolism of amino acids in the brain.

Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aging populations. Although senile plaques and neurofibrillary tangles are well-established hallmarks of AD, changes in cerebral white matter correlate with cognitive decline and may increase the risk of the development of dementia. We used the triple transgenic (3xTg)-AD mouse model of AD, previously used to show that white matter changes precede plaque formation, to test the hypothesis that MRI detectable changes occur in the corpus callosum, external capsule and the fornix. T2-weighted and diffusion tensor magnetic resonance imaging and histological stains were employed to assess white matter in older (11–17months) 3xTg-AD mice and controls. We found no statistically significant changes in white matter between 3xTg-AD mice and controls, despite well-developed neurofibrillary tangles and beta amyloid immunoreactive plaques. Myelin staining was normal in affected mice. These data suggest that the 3xTg-AD mouse model does not develop MRI detectable white matter changes at the ages we examined.

Can Silent Ischemic Cerebral Lesions Affect Cognition of Parkinson's Disease Dementia?

†Background: Several studies have shown that the presence of cerebrovascular lesions may play an important role for determining the severity of the clinical symptoms of dementia. But no study to date has explored the clinical effect of cerebrovascular disease in Parkinson’s disease with dementia (PDD), although cerebrovascular disease is common causes of dementia in elderly population. Therefore we conducted this study to evaluate the relationship between silent cerebrovascular lesions and cognitive decline in PDD. Methods: Only 27 patients with PDD were chosen; 17 patients had PDD with silent cerebral ischemic lesions (PDDI) and 10 patients had PDD without silent cerebral ischemic lesions (pure PDD). These subjects received the global cognitive function testing and were all evaluated with detailed neuropsychological tests including attention, memory, language, and also the visuospatial and frontal function. Results: There were no significant differences between pure PDD and PDDI group on general cognitive functions tests. Regard to mean time duration of suffering from Parkinson motor symptoms and motor function scale, pure PDD group showed more long duration than PDDI group but there was no significant difference between two groups. Furthermore, there were not any significant differences between the two groups on detailed neuropsychological tests. Conclusions: we concluded that silent cerebrovascular lesions do not contribute to neuropsychological severity of PDD, although vascular disease is a common cause of cognitive impairment in the elderly. Thus the results of the present study suggest that factors other than cerebrovascular disease contribute to severity of PDD.

Picture‐Based Memory Impairment Screen for Dementia

To develop and validate a picture-based memory impairment screen (PMIS) for the detection of dementia. Cross-sectional. Outpatient clinics, Baby Memorial Hospital, Kozhikode city in the southern Indian state of Kerala. Three hundred four community-residing adults aged 55 to 94 with a mean education level of 8 years; 65 were diagnosed with dementia. PMIS: a culture-fair picture-based cognitive screen designed to be administered by nonspecialists. Diagnostic accuracy estimates (sensitivity, specificity, positive and negative predictive power) of PMIS cut-scores in detecting dementia (range 0-8). PMIS scores were worse in participants with dementia (1.5) than in controls (7.7, P < .001). At the optimal cut-score of 5, PMIS had a sensitivity of 95.4% (95% confidence interval (CI) = 90.3-100.0%) and a specificity of 99.2% (95% CI = 98.0-100.0%) for detecting dementia. In the 167 participants with <10 years of education, PMIS scores of five or less had a sensitivity of 97.8% (95% CI = 93.6-100.0%) and specificity of 99.2% (95% CI = 97.6-100.0%). The PMIS had better specificity than the Mini-Mental State Examination in detecting dementia, especially in older adults with low education. The PMIS is a brief and reliable screen for dementia in elderly populations with variable literacy rates.

Lack of association between two ACE gene polymorphisms (rs4291 and Alu I/D) and late onset Alzheimer’s disease

Alzheimer’s disease (AD) is a prevalent disorder and the most common cause of dementia in elderly populations. Genetic and environmental factors together play a role in developing late onset Alzheimer's disease (LOAD). According to the recent published papers, ACE is one of the candidate susceptibility genes for LOAD. In this study, allele and genotype frequencies for rs4291 and rs1799752 polymorphisms of ACE gene, for 100 Iranian patients, affected with AD and 100 healthy controls were compared using Chi-square test. No statistically significant differences were found in genotype and allele frequencies of rs4291 and rs1799752 polymorphisms between our LOAD patients and controls. The pair-wise haplotype analysis of rs4291 -240 A/T and rs1799752 Alu I/D polymorphisms were also performed, but no significant associations were identified. Key words : ACE, Alzheimer’s disease, Iranian, association, polymorphism.

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers.

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism.

Role of APP and A&amp;#946; in Synaptic Physiology

Alzheimer's disease (AD) is the most common cause of dementia in aging populations. Although amyloid plaques are the hallmark of AD, loss of synapses and synaptic dysfunction are closely associated with the duration and severity of cognitive impairment in AD patients. Amyloid precursor protein (APP) and its cleavage products including Aβ have been suggested as homeostatic regulators of synaptic activity. APP manipulation and Aβ application, in vitro and in vivo, affect synapse formation and synaptic transmission. Moreover, synaptic dysfunction and learning deficits precede Aβ plaque deposition, suggesting that synaptic alterations may underlie the initial development of the disease. Because of the pivotal role of APP and Aβ in AD pathogenesis, it is essential to understand how APP and Aβ modulate synaptic function. Here, we review the roles that APP and Aβ play at the synapses, with particular focus on recent findings for the importance of APP in synaptogenesis and synaptic function.

Oxidative stress in Alzheimer's and Parkinson's diseases: insights from the yeast Saccharomyces cerevisiae.

Alzheimer's (AD) and Parkinson's (PD) diseases are the two most common causes of dementia in aged population. Both are protein-misfolding diseases characterized by the presence of protein deposits in the brain. Despite growing evidence suggesting that oxidative stress is critical to neuronal death, its precise role in disease etiology and progression has not yet been fully understood. Budding yeast Saccharomyces cerevisiae shares conserved biological processes with all eukaryotic cells, including neurons. This fact together with the possibility of simple and quick genetic manipulation highlights this organism as a valuable tool to unravel complex and fundamental mechanisms underlying neurodegeneration. In this paper, we summarize the latest knowledge on the role of oxidative stress in neurodegenerative disorders, with emphasis on AD and PD. Additionally, we provide an overview of the work undertaken to study AD and PD in yeast, focusing the use of this model to understand the effect of oxidative stress in both diseases.